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NZ544938A - Benzimidazole, benzothiazole and benzoxazole derivatives and their use as LTA4H modulators - Google Patents

Benzimidazole, benzothiazole and benzoxazole derivatives and their use as LTA4H modulators

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Publication number
NZ544938A
NZ544938A NZ544938A NZ54493804A NZ544938A NZ 544938 A NZ544938 A NZ 544938A NZ 544938 A NZ544938 A NZ 544938A NZ 54493804 A NZ54493804 A NZ 54493804A NZ 544938 A NZ544938 A NZ 544938A
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New Zealand
Prior art keywords
ethyl
yloxy
benzothiazol
phenoxy
phenyl
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NZ544938A
Inventor
Frank U Axe
Scott D Bembenek
Christopher R Butler
James P Edwards
Anne M Fourie
Cheryl A Grice
Brad M Savall
Kevin L Tays
Jianmei Wei
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Janssen Pharmaceutica Nv
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Publication of NZ544938A publication Critical patent/NZ544938A/en

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Abstract

Disclosed are Leukotriene A4 hydrolase (LTA4H) inhibitors of Formula (I), wherein the substituents are as defined in the specification, compositions containing them, and their use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and conditions associated with inflammation.

Description

New Zealand Paient Spedficaiion for Paient Number 544938 Docket PRD2089PCT 544938 Received at IPONZ on 4/5/2009 BENZIMIDAZOLE, BENZOTHIAZOLE AND BENZOXAZOLE DERIVATIVES AND THEIR USE AS LTA4H MODULATORS Field of the Invention This invention relates to leukotriene A4 hydrolase (LTA4H) inhibitors for the treatment of inflammation. More particularly, this invention relates to certain benzooxazol-2-yl, benzothiazol-2-yl and 1/-/-benzoimidazoi-2-yl compounds useful as selective inhibitors of the LTA4H enzyme for the treatment of inflammatory conditions.
Background of the Invention Inflammation is normally an acute response by the immune system to invasion by microbial pathogens, chemicals or physical injury. In some cases, 15 however, the inflammatory response can progress to a chronic state, and be the cause of inflammatory disease. Therapeutic control of this chronic inflammation in diverse diseases is a major medical need.
Leukotrienes (LT) are biologically active metabolites of arachidonic acid (B. Samuelsson, Science 1983, 220(4597):568-575) that have been implicated 20 in inflammatory diseases, including asthma (D.A. Munafo et al., J. Clin. Invest. 1994, 93(3): 1042-1050), inflammatory bowel disease (IBD) (P. Sharon and W.F. Stenson, Gastroenterology 1984, 86(3):453-460), chronic obstructive pulmonary disease (COPD) (P.J. Barnes, Respiration 2001, 68(5):441-448), arthritis (R.J. Griffiths et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92(2):517-521; 25 F. Tsuji et al., Life Sci. 1998, 64(3):L51-L56), psoriasis (K. Ikai, J. Dermatol. Sci. 1999, 21(3):135-146; Y.I. Zhu and M.J. Stiller, Skin Pharmacol, Appl. Skin Physiol. 2000, 13(5):235-245) and atherosclerosis (Friedrich, E. B. et al. Arterioscler Thromb Vase Biol 23, 1761-7 (2003); Subbarao, K. et al. Arterioscler Thromb Vase Biol 24, 369-75 (2004); Helgadottir, A. et al. Nat 30 Genet 36, 233-9 (2004); Jala, V.R. et al Trends in Immun. 25, 315-322 (2004)). The synthesis of leukotrienes is initiated by the conversion of arachidonic acid to an unstable epoxide intermediate, leukotriene A4 (LTA4), by 5-lipoxygenase (5-LO) (A.W. Ford-Hutchinson et al., Annu. Rev. Biochem. 1994, 63:383-347). 1 544938 This enzyme is expressed predominantly by cells of myeloid origin, particularly neutrophils, eosinophils, monocytes/macrophages and mast cells (G,K, Reid et al., J. Biol. Chem. 1990, 265(32): 19818-19823). LTA4 can either be conjugated with glutathione by leukotriene C4 (LTC4) synthase to produce the 5 cysteinyl leukotriene, LTC4, or hydrofyzed to the diol, leukotriene B4 (LTB4) (B. Samuelsson, Science 1983, 220(4597):568-575). LTC4 and its metabolites, LTD4 and LTE4, induce smooth muscle contraction, broncho-constriction and vascular permeability, while LTB4 is a potent cherno-attractant and activator of neutrophils.
The stereospecific hydrolysis of LTA4 to LTB4 is catalyzed by leukotriene A4 hydrolase (LTA4H), a zinc-containing, cytosoiic enzyme. This enzyme is ubiquitously expressed, with high levels in small intestinal epithelial cells, lung, and aorta (B. Samuelsson and C.D. Funk, J. Biol. Chem. 1989, 264(33): 19469-19472). Moderate expression of LTA4H is observed in 15 leukocytes, particularly neutrophils (T. Yokomizo et al., J. Lipid Mediators Cell Signalling 1995, 12(2,3):321~332).
Leukotriene B4 is a key pro-infiammatory mediator, able to recruit inflammatory cells, such as neutrophils and eosinophils, as well as activate neutrophils (F.A. Fitzpatrick et al., Ann. N. Y. Acad. Set. 1994, 714:64-74; S.W. 20 Crooks and R.A. Stockley, Int. J. Biochem. Cell Biol. 1998, 30(2); 173—178; A. Klein et a!., J. Immunol. 2000, 164:4271-4276). LTB4 mediates its proinflammatory effects by binding to G protein-coupled receptors, leukotriene B4 receptor 1 (BLT1) and leukotriene B4 receptor 2 (BLT2) (T. Yokomizo et al., Arch. Biochem. Biophys, 2001, 385(2):231—241). The receptor first identified, 25 BLT1, binds LTB4 with high affinity, leading to intracellular signaling and chemotaxis. BLT1 is expressed mainly in peripheral leukocytes, particularly neutrophils, eosinophils, macrophages (Huang, W, W. et al. J Exp Med 188, 1063-74 (1998)) and monocytes (Yokomizo, T., izumi, T. & Shimizu, T. Life Sci 68, 2207-12 (2001)). The murine receptor is also expressed on effector T cells 30 and was recently shown to mediate LTB4-dependent migration of effector CD8+ T cells (Goodarzi, K., Goodarzi, M., Tager, A. M., Luster, A. D. & von Andrian, U. H. Nat Immunol 4, 965-73 (2003).Ott, V.Cambier, J. C., Kappier, J., Marrack, P. & Swanson, B.J. Nat Immunol 4, 974-81 (2003)), early effector 544938 CD4+ T helper type 1 (Th1 ) and Th2 chemotaxis and adhesion to endothelial cells, as well as early effector CD4+ and CD8+ T cell recruitment in an asthma animal model (Tager, A. M. et al.. Nat Immunol 4, 982-90 (2003)).LTB4 receptor BLT2 (S. Wang et al., J. Biol. Chem. 2000, 275(52):40686-40694; T.
Yokomizo et al., J. Exp. Med. 2000, 192(3):421 —431) shares 42% amino acid homology with BLT1, but is more broadly expressed, including in peripheral tissues such as the spleen, ovary and liver, as well as in leukocytes. BLT2 binds LTB4 with lower affinity than BLT1 does, mediates chemotaxis at higher concentrations of LTB4, and differs from BLT1 in its affinity for certain 10 antagonists. While LTB4 receptor antagonists may differ in their affinity for BLT1 versus BLT2, blocking the production of LTB4 using LTA4H inhibitors would be expected to inhibit the downstream events mediated through both BLT1 and BLT2.
Studies have shown that introduction of exogenous LTB4 into normal 15 tissues can induce inflammatory symptoms (R.D.R. Camp et al., Br, J.
Pharmacol. 1983, 80(3):497-502; R. Camp etai., J. Invest. Dermatol. 1984, 82(2):202-204). Elevated levels of LTB4 have been observed in a number of inflammatory diseases including IBD, COPD, psoriasis, rheumatoid arthritis (RA), cystic fibrosis and asthma (S.W. Crooks and R.A. Stockley, Int. J. 20 Biochem. Cell Biol. 1998, 30(2):173-178). Therefore, reduction of LTB4 production by an inhibitor of LTA4H activity would be predicted to have j therapeutic potential in a wide range of diseases.
This idea is supported by a study of LTA4H-deficient mice that, while otherwise healthy, exhibited markedly decreased neutrophil influx in 25 arachidonic acid-induced ear inflammation and zymosan-induced peritonitis models (R.S. Byrum et al., J. Immunol. 1999, 163(12): 6810-6819). LTA4H inhibitors have been shown to be effective anti-inflammatory agents in preclinical studies. For example, oral administration of LTA4H inhibitor SC57461 caused inhibition of ionophore-induced LTB4 production in mouse blood ex 30 vivo, and in rat peritoneum in vivo (J.K. Kachur et al., J. Pharm. Exp. Ther. 2002, 300(2), 583-587). Eight weeks of treatment with the same inhibitor compound significantly improved colitis symptoms in cotton top tamarins (T.D. Penning, Curr. Pharm. Des. 2001, 7(3):163-179). The spontaneous colitis that 3 544938 develops in these animals is very similar to human IBD. The results therefore indicate that LTA4H inhibitors would have therapeutic utility in this and other human inflammatory diseases.
Events that elicit the inflammatory response include the formation of the 5 pro-inflammatory mediator leukotriene B4. Hydrolase LTA4H catalyzes the formation of this mediator,-and LTA4H inhibitors block the production of the pro-inflammatory mediator LTB4, thus providing the ability to prevent and/or treat leukotriene-mediated conditions, such as inflammation. The inflammatory response is characterized by pain, increased temperature, redness, swelling, or 10 reduced function, or by a combination of two or more of these symptoms. Regarding the onset and evolution of inflammation, inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation. and R. Snyderman, Inflammation: Basic Principles and Clinical Correlates, 3rd Edition, (Uppincott Williams & Wilkins, Philadelphia, 1999); V. Stvrtinova, J. Jakubovsky and I. Hulin, "Inflammation and Fever", Pathophysiology Principles of Diseases (Textbook for Medical Students, Academic Press, 1995); Cecil et al., Textbook Of Medicine, 18th Edition (W.B. Saunders Company, 1988); and 20 Steadmans Medical Dictionary. with inflammation can be found in articles such as the following: C. Nathan, Points of control in inflammation, Nature 2002, 420:846-852; K.J. Tracey, The inflammatory reflex, Nature 2002, 420:853-859; L.M. Coussens and Z. Werb, 25 Inflammation and cancer, Nature 2002, 420:860-867; P. Libby, Inflammation in atherosclerosis, Nature 2002, 420:868-874; C. Benoist and D. Mathis, Mast cells in autoimmune disease, Nature 2002, 420:875-878; H.L. Weinerand D.J. Selkoe, Inflammation and therapeutic vaccination in CNS diseases, Nature 2002, 420:879-884; J. Cohen, The immunopathogenesis of sepsis, Nature, 30 2002, 420:885-891; D. Steinberg, Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime, Nature Medicine 2002, 8(11 ):1211-1217. Cited references are incorporated herein by reference.
Examples of textbooks on the subject of inflammation include J, I. Gallin Background and review material on inflammation and conditions related 4 544938 Inflammation is due to any one of a plurality of conditions, such as asthma, chronic obstructed pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), or psoriasis, which are each 5 characterized by excessive or prolonged inflammation at some stage of the disease.
Applicants have discovered benzooxazol-2-yi, benzothiazol-2-yl and 1H-benzoimidazol-2-yl compounds and derivatives thereof; their use as inhibitors of enzymes, such as the LTA4H enzyme, in the formation of pro-inflammatory 10 mediators, such as the LTB4 mediator; also their use for the treatment of inflammatory conditions; and the preparation of pharmaceutical compositions for the treatment of inflammation.
I 544938 Summary of the Invention There are provided by the present invention LTA4H enzyme inhibitors, 5 which have the following general formula (I): (I) wherein X is selected from the group consisting of NR5, O, and S, with R5 being one of H and CH3; Y is selected from the group consisting of CH2, and O; Z is selected from the group consisting of O and bond; W is selected from the group consisting of CH2 and CHR1-CH2, with R1 being 15 one of H and OH, wherein the Reattached carbon member in said CHR1-CH2 is not directly attached to the nitrogen member to which said W is attached; R4 is selected from the group consisting of H, OCH3l CI, F, Br, 1, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently selected from the group consisting of A) H, Ci.7alkyl, C3.7alkenyl, wherein the carbon in said alkenyl that is attached to the nitrogen member has only single bonds, C3-7aikynyl, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, C3-7cycloalkyl optionally benzofused, 25 Cs^cycloalkenyl, -C3-7cycloalkylCi-7aIkyl, -Ci.7alkylC3-?cycloalkyl and phenyl, wherein each of the substituents A) is independently substituted 6 544938 with 0, 1, or 2 RQ, and each of said RQ is a substituent at a carbon member that is at least one carbon member removed from the nitrogen member; B) a substituent HetRa; C) -C-i.yalkylCtOJR*, optionally substituted with CH2RAr or CH2RAf; D) -Ca-salkylCfOJR*, wherein two valence allowed carbon members in the C2-5alkyl of said -C2.5alkyiC(0)Rx are part of a saturated C3-6carbocycie; E) -C2.5alkyIOH wherein two valence allowed carbon members in the C2~salkyl of said -C2.5alkylOH are part of a saturated C3.6carbocycle; F) -C0-4alkylphenyl, wherein the phenyl in said -Co-4alkylphenyI is fused at two adjacent carbon members in said phenyl to Rf, or is benzofused; G) -C0.4alkyiAr6, where Ar6 is a 6-membered heteroaryl having a carbon member point of attachment and having one or two -N= heteroatom members, and benzofused; H) -CfMalkylAr5, where Ar5 is a 5-membered heteroaryl, having one heteroatom member selected from the group consisting of O, S, and >NRy, and having 0 or 1 -N- additional heteroatom member, optionally containing two carbonyl groups, and optionally benzofused; I) -Ci.4alkylAr5, where Ar5 is a 5-membered heteroaryl containing 3 or 4 20 nitrogen members, optionally substituted with Ry, and having a valence allowed site as a point of attachment; j J) -Co^alkylAr6"6, where Ar6"6 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has one or two —N= heteroatom members; 25 K) -C0-4alkylAr6"5, where Ar6"5 is a Co^alkyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRy, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is -N=; and 30 L) one of 2-(4-ethyl-phenoxy)-benzothiazole, 2-{4-ethyl-phenoxy)-benzooxazole, and 2-(4-ethyl-phenoxy)-1H-benzoimidazoie; M) S02C-Malkyl; 7 544938 alternatively R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of 5 i) a 4-7 membered heterocyclic ring HetRb, said 4-7 membered heterocyclic ring HetRb having one heteroatom member that is said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different substitution members, said substituents being selected from the group consisting of -RY, 10 -CN, -C(0)RY, -Co.4alkylC02RY, -C0^aikylC(O)CO2RY1 -C0- 4alkylORY, -CNRM, said 5-7 membered heterocyclic ring HetRG having 0 or 1 carbony! members, and being substituted with 0, 1, or 2 substituents at the same or at different carbon substitution members, said substituents being selected from the group consisting of -C(0)RY, -C02RY -C3-30 4alkylC02RY and Rz; 8 544938 iii) one of imidazolidin-1-yi, 2-imidazolin-1-yl, pyrazoM-yl, imidazoi-1-yl, 2H-tetrazol-2-yl, 1W-tetrazoM~yl, pyrrol-1-yl, 2-pyrrolin-1-yl, and 3-pyrrolin-1-yl, wherein each of said 2H-tetrazoi-2-yi and 1H-tetrazol-1-yl is substituted at the carbon member with 0 or 1 of -C0-4alkylRz, -C0^alkylSRY, -C0-4a!kylCO2RY, and substituent HetRa; and iv) one of 1,2,3,4-tetrahydro-quinofin-1-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yi, indol-1-yl, isoindoi-2-yl, indoiin-1-yl, benzimidazol-1 -yl, 2,8-diaza-spiro[4.5]decan-1 -one-8-yl, 4-{[(2- tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]-methyl}- piperidin-1-yl, 4-{[(2-amino-cyc!obutanecarbonyl)-amino]-methyl}-piperidin-1 -yl, 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yi tert-butyl ester, 4-oxo-1-phenyI-1,3,8-triaza-spiro[4,5]dec-8-yl! and 4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl; wherein substituent HetRa is a 4-7 membered heterocyclic ring having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from said carbon member point of attachment by at least 1 additional carbon member; Rk is selected from the group consisting of H, -C-Malkyi, -C0-4aikylR^r each optionally substituted with 1, 2, or 3 substituents Rn Rl is selected from the group consisting of -C02Rs and -C(0)NRsRs; Rm is selected from the group consisting of Rz, indol-7-yl, -S02RY, -C3. 4aikylC02RY, -C02RY, -C(0)NRz0RY, -C(0)RY, -C(0)CMalkyl0RY, - C0^alkylC(O)NRsRs , Co-4alkylC(0)C02RY, 1,3-dihydro-indol-2-one-1-yi, 1,3-dihydro-benzoimidazol-2-one-1-yis tetrazol-5-yl, 1-RV-1 H-tetrazol-5-yl, RY-triazolyl, 2-RY-2/-/4etrazol-5-yi and -Co-4alkylC{0)N(RY)(S02RY), each optionally substituted with 1, 2 or 3 substituents RN; RN is selected from the group consisting of OCHa, CI, F, Br, I, OH, NH2f CNf CF3l CH3j 0C(0)CH3> and NOz; Rp is selected from the group consisting of RY, -C2-4alkylORY, RAr, -C1.2alkylC02RY -C1.2alky[CONRsRs', indol-7-yi, and -S02CMalkyl; 9 544938 R° is selected from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyi, trichloromethyl, -CN, -Ci^aikyl, -Co^aSkylR^ -Co-4alkylRAr, -C0-4alkylORYI -C0-4alkylCO2RY1 -C0-4alky]NRYRzI -C0.4alkylNRYCORYJ -C0-4alkylNRYCONRYRz, -C0-4alkylNRYSO2RY and-C04aIkylSRY; Rs and Rs are independently selected from the group consisting of H, -C^alkyl, and -Co^aikylphenyi; alternatively, Rs and Rs are taken together with the nitrogen member to which said Rs and Rs are attached to form a 4-7 membered heterocyclic ring having 0 or 1 additional heteroatom member selected from the group consisting of O, S, and >NRY, provided that said 10 additional heteroatom member is separated by at least two carbon members from said nitrogen member to which said Rs and Rs are attached, and provided that where RY is C0.4alkylRAr, then RAr is not substituted with Rl; Rw is selected from the group consisting of RY, and -C3.7cycIoalkyl; 15 Rx is selected from the group consisting of -ORY, -NRYRZ, -Ci^aikyl, and -C0-4alkyiRAr; Ry is selected from the group consisting of H, -Chalky!, -Co-4alkylRAr and -Co-4alkylRAr, each optionally substituted with 1, 2, or 3 substituents RN; Rz is selected from the group consisting of RY, -C2-4alkyiORY 20 -Ci.2alkylC02RY, -C1.2alkylC(0)NRsRs', and -C2-4alkyiNRsRs'; when Ry and Rz are attached to a nitrogen member, RY and Rz are selected as defined above, or RY and Rz are taken together with the RY- and Rz-attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group 25 consisting of O, S, and >NRM, said 4-7 membered heterocyclic ring HetRd having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring HetRd having 0 or 1 valence allowed carbon members substituted with at least one of RM, -C02H, and -C0-ialkyiORY; RAr is a moiety with a carbon member attachment point and said moiety is 30 selected from the group consisting of phenyl, pyridyl, pyrimidyl, and pyrazinyl, wherein each valence allowed carbon member in each of said moieties is independently substituted with at least one of 0,1, 2 or 3 RN, and 0 or 1 RL; 544938 RAr is a 3-8 membered ring, having 0,1 or 2 heteroatom members selected from the group consisting of 0, S, N, and >NRY, having 0, 1, or 2 unsaturated bonds, having 0 or 1 carbonyl members, wherein each valence allowed member in each of said rings is independently substituted with 0, 1, 5 or 2 RK; and Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members; or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceutical^ acceptable salt, ester, or amide thereof, 10 Embodiments of the present invention comprise new compounds that are LTA4H enzyme inhibitors and have the general formula (II): (I!) or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or i pharmaceutical^ acceptable salt, ester, or amide thereof, wherein R4, R6, X, Y, Z, and W are defined as in compound of formula (I), R2 is defined as R2 in compound of formula (I), and R3 is defined as R3 in compound of formula (1), provided that (a) at least one of said R2 and R3 is not ethyl when one selection in the group consisting of selections (s1), (s2), (s3), and (s4), is satisfied, and each of said selections is specified as (s1): R4 is H, Z is O, W is CH2, Y is CH2, and X is S; (s2): R4 is H, Z is O, W is CH2, Y is CH2, and X is NH; (s3): R4 is H, Z is O, W is CH2, Y is O, and X is S; 11 544938 (s4); R4 is 5-chloro, Z is O, W is CH2i Y is CHZs and X is S; (b) further provided that when Z is bond, Y is CH2) W is CHR1-CH2, R1 is H, and one of R2 and R3 is 1H-imidazol-2-yI, then the other of R2 and R3 is selected from A1), B)-L), wherein B)-L) are as defined above for compound of 5 formula (I), and A1) consists of H, C3.7alkenyl, wherein the carbon in said C3. 7alkenyl that is attached to the nitrogen member has only single bonds, C3. /alkynyl, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, C3.7cycIoalkyl optionally benzofused, C5. 7cycloalkenyl, -C3.7cycloalkylCi-7a!kyl, -C-i-7alkylC3-7cycloalkyl; and (c) further provided that when X is S, Y is O, Z is bond, and W is CH2, then one of R2 and R3 Is not XCG when the other is Chalky!, wherein XCG is the group CN H-ch^ N GO (XCG) HC16 wherein HC16 is one of H, Chalky!, haloCi^alkyi, ally!, and Ci-6alkoxymethyl, and GO is a group attached by a carbon member that has a =0 substituent forming an amido group (>N-C(0)-) with the nitrogen member to wich s^id GO group is attached.
Other embodiments of the present invention comprise new compounds that are LTA4H enzyme inhibitors and have the general formula (III): 12 544938 R 2" W N / \3" (III) or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceutical^ acceptable salt, ester, or amide thereof, wherein R4, R6, X, Y, Z, and W are defined as in compound of formula (I), R2 is defined as R2 in compound of formula (I), and R3 is defined as R3 in compound of formula (1), provided that (a) said R2 and RJ further satisfy one of the following: is S; i3" , (e1): at least one of said R2 and R3 is not Chalky!, when Z is O and X (e2): none of R* and R3 is Ci,4aIkylC{0)RA, with RA being one of Cn„ 4alkyl, OH, -OC-Malkyl, -OC0-4alkylRAr, or ~NRYRY, when Y is O, Z is bond, and R2 is different from R3 ; and (e3): none of R2 and R3 is -Ci^alkylCN, when Y is O, Z is bond/and R2" is different from R3; and (b) further provided that when X is S, Y is O, Z is bond, and W is CH2, then one of R2 and R3 is not XCG when the other is Chalky!, wherein .XCG is the group CN j—<-CH2^j (XCG) -4 N GO HC16 13 544938 wherein HC16 is one of H, Ci-©alkyl, haloCi-ealkyI, allyl, and Ci-6alkoxymethyl, and GO is a group attached by a carbon member that has a =0 substituent forming an amido group (>N-C{0)-) with the nitrogen member to which said GO group is attached.
Isomeric forms of the compounds of the foregoing formulae, and of their pharmaceutical^ acceptable salts, amides and esters, are encompassed within 10 the present invention, and reference herein to one of such isomeric forms is meant to refer to at least one of such isomeric forms. One of ordinary skill in the art will recognize that compounds according to this invention may exist, for example in a single isomeric form whereas other compounds may exist in the form of a regioisomeric mixture.
Whether stated explicitly or not in any part of the written description and claims, it is understood that each substituent and member assignment in the context of this invention is made independently of any other member and substituent assignment, unless stated otherwise. By way of a first example on substituent terminology, if substituent Sample is one of S-t and S2, and 20 substituent Sample is one of S3 and S4, then these assignments refer to embodiments of this invention given according to the choices S1eXampie is S., and S example 'S S3; S example IS Si and S example IS S4; S example IS S2 and S example 'S S3; S1 example is S2 and S2exampie is S4; and equivalents of each one of such choices. The shorter terminology "Sample is one of Si and S2) and S2exampie is one of S3 25 and S4" is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent R assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as X, Y, Z, and W, 30 and the index n.
Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and 544938 equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent SeXampie is one of S<\, S2, and S3, this listing refers to embodiments of this invention for which Sexampie is St; SeXampie is s2; Sexampie is S3; Sexampie is one of Si and S2; Sexampie is one of Si and S3; Sexampie is one of S2 and S3; Sexampie is one of Si, S2 and S3; and Sexampie is any equivalent of each one of these choices. The shorter terminology "Sexampie is one of Si, S2l and S3" is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various 10 substituent R assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as X, Y, Z, and W, and the index n.
The nomenclature "CH" with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each 15 and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C1-3 refers independently to embodiments that have one carbon member (C-j), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).
The term Cn_malkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n n.
When any variable referring to a substituent, compound member or index, occurs more than once, the full range of assignments is meant to apply 25 to each occurrence, independently of the specific assignment(s) to any other occurrence of such variable.
According to the foregoing interpretive considerations on assignments and nomenclature, it is understood that explicit reference herein to a set implies, where chemically meaningful and unless indicated otherwise, 30 independent reference to embodiments of such set, and reference to each and every one of the possible embodiments of subsets of the set referred to explicitly.
Docket PRD2089PCT 544938 Described herein are methods for inhibiting LTA4H enzyme activity with such compounds, and pharmaceutical compositions containing such compounds and methods of using such compositions in the treatment or prevention of conditions that are mediated by LTA4H enzyme activity.
Pharmaceutical compositions according to the present invention include at least one of the compounds of the present invention. If more than one of such compounds is included in a composition, the therapeutically effective amount may be a jointly effective amount. As such inhibitors of the LTA4H enzyme, compounds and compositions according to the present invention are 10 useful in the prevention, inhibition, or treatment of inflammation.
The invention also features a pharmaceutical composition for treating or preventing an LTA4H-mediated condition in a subject, comprising a therapeutically effective amount of at least one LTA4H modulator selected from compounds of formulae (I), (II), and (11), enantiomers, diastereomers, 15 racemates thereof, pharmaceutical^ acceptable salts, amides and esters thereof, tn addition, the invention features a pharmaceuticai composition for inhibiting inflammatory response in a subject, comprising a therapeutically effective amount of at least LTA4H inhibitor selected from compounds of formulae (I), (11), and (111), enantiomers, diastereomers, racemates thereof, 20 pharmaceutically acceptable salts, amides and esters thereof. The invention additionally features an anti-inflammatory composition, comprising a therapeutically effective amount of at least one anti-inflammatory compound selected from compounds of formulae (1), (II), and (111), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides 25 and esters thereof.
Also described herein are methods for treating or preventing inflammation in a subject, comprising administering to the subject in connection with an inflammatory response a pharmaceutical composition that comprises a therapeutically effective amount of at least one anti-inflammatory compound 30 selected from compounds of formulae (I), (II), and (111), enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof. The invention also features methods for treating or 16 Docket PRD2089PCT 544938 preventing an LTA4H-mediated condition in a subject, comprising administering to the subject a pharmaceutical composition that comprises a therapeutically effective amount of at least one LTA4H modulator selected from compounds of formulae (!), (II), and (III), enantiomers, diastereomers, 5 racemates thereof, pharmaceutically acceptable salts, amides and esters thereof. Furthermore, described herein are methods for inhibiting inflammation in a subject, comprising administering to the subject a pharmaceutical composition that comprises a therapeutically effective amount of at least one LTA4H inhibitor selected from compounds of formulae (I), (il), and (Ml), 10 enantiomers, diastereomers, racemates thereof, pharmaceutically acceptable salts, amides and esters thereof.
Described herein are methods for the treatment, prevention and/or inhibition of conditions that are associated with and/or cause inflammation, such as any one or a plurality of the followoing conditions: Asthma, chronic 15 obstructed pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), or psoriasis, which are each characterized by excessive or prolonged inflammation at some stage of the disease.
Additional features and advantages of the invention will become 20 apparent from the detailed description below, including examples, and the appended claims. 544938 Detailed Description of the Invention The present invention is directed to compounds of formula (I), (II), or (III) as herein defined, enantiomers, diastereomers, racemates thereof, 5 pharmaceutically acceptable salts, amides and esters thereof, pharmaceuticai compositions that contain at least one of such compounds, methods of using, including treatment and/or prevention of conditions such as those that are mediated by LTA4H, and methods of making such pharmaceutical compositions.
The following terms are defined below, and by their usage throughout the disclosure, "Alkyl" includes straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, 15 sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl does not include cycloalkyl.
"Alkeny!" includes straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp2). Unless indicated otherwise by the prefix that indicates the number of carbon members, alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-20 methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. j "Alkynyl" includes straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Unless indicated otherwise by the prefix that indicates the number of carbon members, alkynyls 25 include ethynyf, propynyls, butynyts, and pentynyis. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein.
"Alkoxy" includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes 30 methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. "Aminoalkyl", "thioalkyi", and "sulfonylalkyl" are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO2. 18 544938 Unless indicated otherwise by the prefix that indicates the number of carbon members, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyctooctyi, and so on.
Unless indicated otherwise by the prefix that indicates the number of 5 members in the cyclic structure, "heterocyclyl", "heterocyclic" or "heterocycle" is a 3- to 8-member aromatic, saturated, or partially saturated single or fused ring system that comprises carbon atoms wherein the heteroatoms are selected from N, O, and S. Examples of heterocyclyls include thiazoylyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyf, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, 10 pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyi, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazoiidinyl, pyrazolinyl, piperidyl, piperazinyl, indoiinyl, and morpholinyl. For example, preferred heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and more 15 preferably, piperidyl.
Substitution positions are referred to in conventional terms. For example, piperidine and piperazine group substitution positions are numberd as follows: "Carbocycle" is a cycloalkyl or a partially saturated cycloalkyl that is not benzo .
"Aryl" includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and so on, any of which may be optionally substituted. Aryl also includes arylaikyl groups such as benzyl, phenethyl, and phenylpropyl. Aryl includes a ring 25 system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated. Examples of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyf, indolyl, benzofuranyf, isoquinolinyl, and so 19 544938 on. Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyj, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyi.
"Halo" includes fluoro, chloro, bromo, and iodo, and is preferably fluoro 5 or chloro.
The term "carbonyl" refers to a >C=0 moiety, such that when this term is characterized as being part of a chain or cyclic structure, the carbon member in the carbonyl group is taken as being one of the carbon members of such chain or cyclic structure.
As in standard chemical nomenclature, the group phenyl is herein referred to as "phenyl" or as "Ph".
It is understood that substitutions and combinations of substitutions recited herein, whether stated explicitly or not, refer to substitutions that are consistent with the valency of the member being substituted. Terms such as 15 "valence allowed site", "valence allowed member" and morphological variations thereof are used herein in this sense. For example, "valence allowed" when applied to a carbon member refers to the tetravalency of C; it refers to the trivalency of N when applied to a nitrogen member; and it refers to the four bonds of a nitrogen member that is conventionally characterized with a positive 20 electric charge. Valence allowed options are part of the ordinary skill in the art.
"Patient" or "subject" includes mammals such as human beings ^nd animals (e.g., dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient is a human being. 25 "Composition" includes a product comprising the specified ingredients in the specified amounts, including in the effective amounts, as well as any product that results directly or indirectly from combinations of the specified ingredients in the specified amounts.
"Therapeutically effective amount" or "effective amount" and 30 grammatically related terms mean that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, 544938 medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
Table of Acronyms Term Acronym Tetrahydrofuran THF N, N-Dimethylformamide DMF N.N-Dimethylacetamide DMA Dimethyl sulfoxide DMSO tert-Butylcarbamoyl BOC Bovine serum albumin BSA High-pressure liquid chromatography HPLC Thin layer chromatography TLC Compounds of formula (I), (II), or (III) comprise compounds that satisfy any one of the combinations of definitions given herein and equivalents thereof.
It is understood that some compounds refered to herein are chira! and/or have geometric isomeric centers, for example E~ and Z- isomers. The present invention encompasses all such optical isomers, including diasteroisomers and racemic mixtures, and geometric isomers that possess the activity that characterizes the compounds of this invention. In addition, certain 15 compounds referred to herein can exist in solvated as well as unsolvated forms. It is understood that this invention encompasses all such soivated and unsolvated forms that possess the activity that characterizes the compounds of this invention. Compounds according to the present invention that have been modified to be detectable by some analytic technique are also within the scope 20 of this invention. An example of such compounds is an isotopically labeled compound, such as an 18F isotopically labeled compound that may be used as a probe in detection and/or imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Another example of such compounds is an isotopically labeled 21 544938 compound, such as a deuterium and/or tritium labeled compound that may be used in reaction kinetic studies.
It is understood that substitutions and combinations of substitutions recited herein, whether stated explicitly or not, refer to substitutions that are 5 consistent with the valency of the member being substituted. For example, a substitution applied to a carbon member refers to the tetravalency of C; it refers to the trivalency of N when applied to a nitrogen member; and it refers to the four bonds of a nitrogen member that is conventionally characterized with a positive electric charge. Valence allowed options are part of the ordinary skill 10 in the art.
The "pharmaceutically acceptable salts, amides or and esters thereof refer to those salts, amides and ester forms of the compounds of the present invention that would be apparent to the pharmaceutical chemist, i.e., those that are non-toxic and that would favorably affect the pharmacological properties of 15 said compounds of the present invention. Those compounds having favorable pharmacological properties would be apparent to the pharmaceutical chemist, i.e., those that are non-toxic and that possess such pharmacological properties to provide sufficient palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, that are also important in the 20 selection are cost of raw materials, ease of crystallization, yield, stability, hygroscopicity, and flowability of the resulting bulk drug. j Representative acids and bases that may be used in the preparation of pharmaceutically acceptable salts include the following; acids including acetic acid, 2,2-dichloroiactic acid, acylated amino acids, 25 adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+}-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, 30 fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-giutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, {+}-L-lactic acid, (±)-DL-iactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic 22 544938 acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicy)ic acid, sebacic acid, stearic 5 acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 10 1H-imidazole, L-fysine, magnesium hydroxide, 4-(2-hydroxyethyl)~morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
See, for example, S.M. Berge, eta/,, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66:1-19, which is incorporated herein by reference. Examples of 15 suitable esters include Ci-7alkyl, C5_7cycloaIkyl, phenyl, substituted phenyl, and phenylCi.6alkyl- esters. Preferred esters include methyl esters.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the 20 required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but that converts to the specified compound in vivo after administration to the patient. Conventional 25 procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Embodiments of this invention, where X is O, are made according to the 30 synthetic methods outlined in Schemes A-D and F-L, have demonstrated LTA4H inhibitory activity, and are selected from the group consisting of: 23 544938 Example Compound 11 2-[4-(2-Piperidin-1 -yl-ethoxy)-phenoxy]-benzooxazole; 13 (1 -{2-[4-(Benzooxazol-2~yloxy)-phenoxy]ethyl}-piperidin-4-yl)-methanol; 14 1 -{2-[4-{Benzooxazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-ol; 16 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine; 21 (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy)-ethyI}-piperidin-2-yl)-methanoi; 27 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyI}-4-phenyl-piperidin-4-ol; 28 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-benzy[-piperidin-4-ol; 29 2-[4-(2-Piperidin-1 -yl-ethylj-phenoxyj-benzooxazole; {3-[4-(Benzooxazol-2-yloxy>phenyl]-propyl}-cyclohexyl-ethyl-amine; 36 1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyI}-piperidin-4-oi; 40 1 -{3-[4-(Benzooxazoi-2-yloxy)-phenoxy]-2-hydroxy-propyl}-4-phenyl-piperidin-4-ol; 41 1 -[2-(4~Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylic acid ethyl ester; 44 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzooxazole; j 45 {3-[4-(BenzooxazoI-2-yioxy}-phenoxy]-propyi}-dimethyl-amine; 46 {2-[4-{Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine; 47 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzooxazole; 53 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol; 54 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-cycIohexyi-ethyl-amine; 55 2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazoIe; 56 1-{2-[4-(Benzooxazol-2-yioxy)-phenoxy)-ethyl}-4-phenyl-piperidine-4-carbonitrile; 57 1 -(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-yl)-ethanone; 24 544938 58 2-{4-[2-{4-Methyl-piperidin-1-yi)-ethoxy]-phenoxy}-benzooxazole; 59 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chIoro-phenyl)-piperidin-4-ol; 60 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phertyi}-piperidin-4-ol; 61 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-4-{4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol; 62 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyI}-4-benzyl-piperidin-4-oJ; 63 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-cyctohexyl-methyi-amine; 64 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyciopropylmethyl-propyi-amine; 65 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethy!}-butyl-ethyl-amine; 66 2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-benzyl-amino)-ethanol; 67 2-{4-[2~{4-Benzyl-piperidin-1-yi)-ethoxy]-phenoxy}-benzooxazoie; 68 (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3"y[)-methanol; 69 2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-propyl-amino)-ethanol; 77 2-[4-(2-Azetidin-1 -yl-ethoxy)-phenoxy]-berizooxazole; 78 A/-(1-{2-[4-(Benzooxazol-2-y]oxy)-phenoxy3-ethyl}-piperidin-4-yl)-2-phenyl-acetamide; 79 1 -{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyI}-piperidine-3-carboxylic acid ethyl ester; 86 2-{4-[3-(4-Phenyl-piperidin-1-yl)-propoxy]-phenoxy}-benzooxazole; 88 1-{2-[4-(Benzooxazol-2-yioxy)-phenyi]-ethyl}-4-phenyi-piperidin-4-ol; 89 {2-[4-(Benzooxazol-2-yloxy)-phenyI]-ethyl}-cyciohexyl-ethyl-amine; 90 2-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenoxy]-benzooxazole; 91 2-[4-(2-Azepan-1 -yl-ethyl)-phenoxy]-benzooxazoie; 544938 92 {2-[4-(Benzooxazoi-2-yloxy)-phenyI]-ethyI}-cyclopropylmethyl~ propyl-amine; 93 {2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine; 94 1-{2-[4-(Benzooxazol-2-yloxy)-phenyi]-ethyl}-piperidin-4-ol; 96 1 -{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethy[}-piperidine-4- carboxylic acid methyl ester; 116 1 -{3-[4-{Benzooxazol-2-yloxy)-phenyl]-propy!}-4-phenyl-piperidin-4-ol; 120 2-[4-(3-Piperidin-1 -yi-propyl)-phenoxy]-benzooxazole; 121 {3-[4-(Benzooxazol-2-yioxy)-phenyl]-propyl}-dibutyl-amine; 122 {3-[4-(Benzooxazol-2-yioxy)-phenyl]-propyl}-cycIopropyimethyl-propyl-amine; 135 1 -[4-{Benzooxazol-2-yloxy)-phenoxy3-3-pyrrolidin-1 -yl-propan-2-ol; 136 1 -[2-(4-Benzooxazol-2-ylmethyI-phenoxy)-ethyl]-4-phenyl-piperidin-4-oI; 137 1 -[2-(4-Benzooxazol-2~ylrnethyl-phenoxy)-ethyi]-piperidine-4-carboxylic acid amide; 271 2-(4-Piperidin-1-ylmethyl-pherioxy)-benzooxazole; 481 2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzooxazole; and 484 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyf}-diethyi-amine.
■ I Other embodiments of this invention, where X is Ss are made according to the synthetic methods outlined in Schemes A-G, and l-L, have demonstrated LTA4H inhibitory activity, and are selected from the group 5 consisting of: Example Compound 12 {2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyi}-diethyl-amine; 1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-oi; 17 1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidine-4-carboxylic acid ethyl ester; 26 544938 18 1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid; 19 (1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrrolidin-1 -yl-methanone; 3-[(1-{2-[4-(Benzothiazo]-2-yIoxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-propionic acid ethyl ester; 22 1-{2-[4-(Benzothiazol-2~yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid amide; 23 1 -(1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidirs-4-yl)-pyrrolidin-2-one; 24 1 '-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1 s4']bipiperidinyl-2-one; 8-{2-[4-(Benzothiazol-2~yioxy)-phenoxy]-ethy!}~2t8-diaza-spiro[4.5]decan-1 -one; 26 2-[4-(3-Pyrrolidin-1 -yl-propoxy)-phenoxy]-benzothiazole; {2-[4-(Benzothiazo[-2-yloxy)-phenyi]-ethyl}-cyclohexyl-ethyl-amine; 31 1 -{2-[4-{Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidine-3-carboxylic acid amide; 32 1-{1-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyI}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one; 33 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester; 34 (l-{2-[4-(Benzothiazo!-2-yloxy)-phenyl]~ethyl}-piperidin-4-yi)-(4-methyl-piperazin-1 -yl)-methanone; 42 1-[2-{4-Benzothiazol-2-ylmethyl-phenoxy)-ethy!]-piperidine-4-carboxylic acid methyl ester; 43 3-({2-[4-(BenzothiazoJ-2-y!oxy)-phenoxy]-ethyl}-cyclopropyl-amino)-propionic acid; 48 {2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-dimethy!-amine; 49 2-[4-{2-Pyrrolidin-1 -yl-ethoxy)-phenoxy]-benzothiazole; 50 {3-[4-(Benzothiazol-2-yIoxy)-phenoxy]-propyl}-dimethyl-amine; 51 2-[4-(2-Azepan-1 -yl-ethoxy)-phenoxy]-benzothiazoIe; 27 544938 52 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-benzothiazoIe; 70 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyi}-4-phenyl-piperidin-4-ol; 71 {2-[4-(Benzothiazol-2-yIoxy)-phenoxy]-ethyl}-cyclohexyi-ethyl-amine; 72 1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-4-(4-chIoro-phenyl)-piperidin-4-ol; 73 {2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethy!}-dibutyl-arriine; 74 1 -{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol; 75 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy[}-4-(4-chloro-3-trifiuoromethyl-phenyl)-pipendii>4-oi; 76 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol; 80 1 '-{2-[4-{Benzothiazoi-2-yloxy)~phenoxy]-ethyl}-[1,4']bipiperidine; 81 (1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-yl)-methanol; 82 W-(1-{2-[4-(BenzothiazoI-2-yIoxy)-phenoxy]-ethy!}-piperidin-4-yl)-2-phenyl-acetamide; 83 1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy[}-[1 ^'jbipiperidinyl-2-one; j . 84 2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazole; 85 2-(4-{2-[4-(2-Morpholin-4-yI-ethyl}-piperazin-1-yl]-ethyl}-phenoxy)-benzothiazole; 87 1 -{3-[4-(Benzothiazol-2-yloxy)-phenoxy]-propyl}-4-pheriyl-piperidin-4-ol; 95 1 -{2-[4-(BenzothiazoI-2-y[oxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ol; 97 2-[4-(2-Pyrrolidin-1 -yl-ethyi)-phenoxy]-benzothiazoie; 98 2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzothiazole; 99 {2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyc!opropyimethyi-propyl-amine; 28 544938 100 {2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyJ}-dibutyi-amine; 101 2-[4-{2-Piperidin-1 -yl-ethyl)-phenoxy]-benzothiazole; 102 1 -{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyI}-piperidin-4-ol; 103 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethy!}-piperidine-4-carboxylic acid methyl ester; 104 1 -{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid amide; 105 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-piperidine-3-carboxylic acid ethyl ester; 106 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-4-phenyl-piperidine-4-carboxyfic acid ethyl ester; 107 (1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-acetic acid ethyl ester; 108 1 -(1 -{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidin-4-yl}-1,3-dihydroindol-2-one; 109 1-(1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-pyrrolidin-2-one; 110 N-{ 1 -{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-yl)-2-phenyl-acetamide; 111 8-{2-[4-(Benzothiazol-2-yloxy)~phenyl]-ethyl}-2t8-diaza-spiro[4.5]decan-1-one; 112 1 -{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-piperidin-3-ol; 113 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyJ}-piperidine-4-carboxylic acid ethyl ester; 114 1 '-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-[1,4']bipiperidine; 115 2-{4-[2-(4-Methyl-piperazin~1 -yl)-ethyl]-phenoxy}-benzothiazole; 143 2-(4-{2-[4-(1 -Benzyl-1 H-tetrazol-5-yl)-piperidin-1 -yl]-ethoxy}-phenoxy)-benzothiazole; 144 4-(1-{2-[4-(Benzothiazoi-2-yloxy)-phenyi]-ethyi}-piperidine~4-carbonyl)-piperazine-1-carboxylic acid fe/t-butyi ester; 146 2-(4-{2-[4-(2-Morpholin-4-yi-ethyl)-piperazin-1 -yl]-ethyl}-phenoxy)-benzothiazole; 29 544938 147 1 -[2-(4-Benzothiazol-2-ylmethyI-phenoxy)-ethyI]-piperidine-4-carboxylic acid amide; 148 1 -{1 -[2-(4-Benzothiazol-2-yimeihyl-phenoxy)-ethyl]-piperidin-4-y!}-pyrrolidin-2-one; 149 1-[4-(1-{2-[4-(Berizothiazol-2-yloxy)-phenyi]-ethyl}-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone; 150 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidine-4-carboxylic acid; 151 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperidin-4-y!)-pyrrolidine-2-thione; 152 2-(4-{2-[4-(Benzothiazoi-2-yIoxy)-phenoxy]-ethyI}-piperazin-1 -yi)-ethanol; 153 2-(4-{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyi}-piperazin-1 -yl)-1-pyrrolidin-1-yl-ethanone; 154 2-{4-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperazin-1 -yl)~ 1 -morpholin-4-yl-ethanone; 155 1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyi}-piperidine-3" carboxyiic acid; 156 1 -{2-[4-(Benzothiazol-2-yioxy)-pheny!]-ethyI}-piperidine-2-carboxylic acid; 157 (1-{2-[4-(Benzothiazol-2-yloxy)-pheny[]-ethyl}-piperidin-3-yI)-^cetic acid; 158 (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperidin-4-yI)" acetic acid ethyl ester; 159 (1 -{2-[4-{Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-carbamic acid tert-butyl ester; a 160 (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-yl)-acetic acid; 161 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-yl)-methanol; 162 ({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-amino)-acetic acid methyl ester; 544938 163 (4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy[}-piperazin~1 -y!)-acetic acid; 164 1 -(1 -{2-[4-(Benzothiazol-2-yIoxy)-phenoxy]-ethyl}-piperidin-4-yI)-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester; 166 1 -(1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-5-oxo-pyrrolidine-2-carboxylic acid; 167 4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperazin-1 -yl)-phenol; 168 A/-{1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperidin-4-yl)-4-chloro-W-cyclopropyl-benzene sulfonamide; 170 3-{{2-[4-(Benzothiazol~2-yloxy)-phenoxy]-ethyl}-cyclopropyimethyl-amino)-propionic acid; 171 3-({2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyl}-isopropyl-amino)-propionic acid; 172 1-{2-[4-(Benzothiazol~2-yloxy)-phenoxy]-ethyi}-piperidin-4-ylamine; 173 3-[{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-{1 -methyl-piperidin-4-yl)-amino]-propionic acid; 174 3-({2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethy!}-benzyi-amino)-propionic acid; 175 3-((1-Acetyl-piperidin-4-ylH2-[4-(benzothiazol-2-yioxy)-phenoxy]-ethyl}-amino)-propionic acid; 176 4-(1 -{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1 H-tetrazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester; 177 3-{{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-cyclopropyl-amino)-propionic acid; 178 3-((1 -Acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-amino)-propionic acid; 179 3-[{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-( 1 -methyl-piperidin-4-yl)-amino]-propionic acid; 180 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-cyclopropyimethyl-amino)-propionic acid; 31 544938 181 182 183 184 185 186 187 188 189 190 192 193 194 195 196 197 3-{{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropyl-amino)-propionic acid; 2-(4-{2-[4-{Benzothiazol-2-yIoxy)-phenyl]-ethyI}-piperazin-1-yl)-1-pyrrolidin-1 -yl-ethanone; (R)-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylic acid; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yi)-1,3" dihydro-benzoimidazol-2-one; 2-(4"{2-[4-(6-Methyl-pyridin-2-y!)-piperazin-1-yl]-ethyl}-phenoxy)-benzothiazole; 2-{4-[2-(4-Ethanesulfonyl-piperazin-1-yi)-ethyl]-phenoxy}-berizothiazole; 2-(4-{2-[4-(Benzothiazol-2-yIoxy)-phenyl]-ethyI}-piperazin-1-yl)-1-morpholin-4-yl-ethanone; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-methyl-amino)-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyi3-ethyi}-cyciopentyl-amino)-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-cyciobutyl-amino)-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-benzyl-amino)-propionic acid; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yi)-{4- hydroxymethyl-piperidin-1-yIKnethanone; {2-[4-(Benzoth iazol-2-yloxy )-p h enyl]-ethyl}-cyclopro pyl-a mine; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-[4- {2-hydroxy-ethyl)-piperazin-1 -yl]-methanone; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy!}-piperidin-4-yl)-[4- (2-hydroxy-ethy!)-piperidin-1-yl]-methanone; 2-({2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyI}-cyclopropyl-amino)- ethanoi; 32 544333 198 3-({2-[4-(Benzothiazol-2-yioxy)-pheny!]-ethyi}-cyclopropyl-amino}-propan-1-ol; 199 4-({2-[4-(Benzothiazol-2-y[oxy)-phenyI]-ethyl}-cycIopropyl-amino)-butyric acid; 200 3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-propionic acid; 201 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-cyclopropyl-amino)-butyronitrile; 202 3-{1-{2-[4-(Benzothiazol-2-yioxy)-phenylJ-ethyl}-piperidin-4-yI)-propionic acid; 203 [(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl-amino]-acetic acid; 204 3-(4-{2-[4-{Benzothiazol-2-yioxy)-phenoxy]-ethyi}-piperazin-1-yl)-phenol; 205 2-(4-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazole; 206 2-{4-[2-(5-Piperidin-4-yl-tetrazoM -yI)-ethoxy]-phenoxy}-benzothiazoie; 207 (S)-1~(1-{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyi}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-orie; 208 {2-t4-(Benzothiazol-2-yloxy)-phenyi]-ethyI}-cycIopropy!methyl-amine; 209 2-[({2-[4-(Benzothiazol-2-y!oxy)-phenyi]-ethyl}-cyclopropyl-amino)-methylj-cyclopropanecarboxylic acid ethyl ester; 210 4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazine-1-carbony[)-benzoic acid ethyl ester; 211 2-[({2-[4-(Benzothiazol-2-yloxy)-pheriyl]-ethyl}-cyclopropyl-am!no)-methyl]-cyclopropanecarboxylic acid; 212 1-({2-[4-(Benzothiazol-2-yloxy)-phenylj-ethyi}-cyc!opropyi-amino)-propan-2-ol; 213 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyc!opropyl-amino)-1,1,1 -trifluoro-propan-2-ol; 33 544938 214 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-eyclopropyl-amino)-propionamide; 215 3-({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyl-amino)-propane-1,2-diol; 216 2-{4-[2-(5-Phenyl-tetrazol-2-yI)-ethoxy]-phenoxy}-benzothiazoIe; 217 2-{4-[2-(5-Phenyl-tetrazoi-1 -yi)-ethoxy]-phenoxy}-benzothiazoie; 218 A/-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-A/-cyciopropyl-2-(2H-tetrazol-5-yl)-acetamide; 219 (S)-3-({2-[4-(Benzothiazol-2-yloxy)~pheriyl]-ethyl}-cyciopropyl-amino)-2-methyl-propan-1 -ol; 220 (/?)-3-({2-[4-{Benzothiazol-2-yioxy)-pheriy!]-ethyi}-cyclopropyl-amino)-2-methyl-propan-1-ol; 221 2~{4-[2-(5-Methylsulfanyl-tetrazoi-2-yl)-ethoxy]-phenoxy}-benzothiazole; 222 2-{4-[2-(5-Methylsulfanyl-tetrazo!-1 -yl)-ethoxy]-phenoxy}-benzothiazole; 223 2-[4-(2-T etrazol-2-yl-ethoxy)-phenoxy]-benzothiazo!e; 224 2-[4-(2-T etrazo!-1 -yl-ethoxy)-phenoxy]-benzothiazole; 225 (1R,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethylamino}-cyclohexanecarboxylic acid; 226 {1 S,2R)-2-{2-[4-(Benzothiazoi-2-yioxy)-phenyl]-ethyiamino}- j cyclohexanecarboxylic acid; 227 <1/?,2R)-2-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethylamino}~ cyclohexano!; 228 (1S,2/?)-2-{2-[4-(Benzothiazol-2-yIoxy)-phenyI]-ethylamino}-cyciohexanol; 229 4-(1-{2-[4-(Benzothiazoi-2-yloxy)-pheny|]-ethyl}-piperidin-4-yl)-butyric acid; 250 1 -[4-(Benzothiazol~2-yloxy)-benzyI]-piperidine-4-carboxylic acid; 251 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yI}-pyrrolidin-2-one; 252 2-(2-Fluoro-4-piperidin-1 -ylmethyl-phenoxy)-benzothiazoie; 34 544938 253 N-{1-[4-(Benzothiazol-2-yIoxy)-benzyI]-piperidin-4-yl}-2-hydroxy-acetamide; 254 1-(2-{[4-(Berizothiazol-2-yIoxy)-benzyl]-cycIopropyl-amino}-ethyl)-4-hydroxy-pyrrolidin-2-one; 255 N-{1-[4-{Benzothiazol-2-yloxy)-benzyi]-piperidin-4-yl}-N-methyl-methanesulfonamide; 256 2-{4-[4-(1 H-Tetrazol-5-yl)-piperidin-1 -ylmethylj-phenoxy}-benzothiazoie; 257 1 -{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1 -yl}-2-hydroxy-ethanone; 258 N-{1-[4-{Benzothiazol-2-yloxy)-benzy!]-piperidin-4-ylmethyl}~ methanesulfonamide; 259 3-{1-[4-(Benzothiazol-2-yioxy)-benzyl]-psperidin-4-yl}-oxazoiidin-2-one; 260 4-{1-[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl}-morpholin-3-one; 261 {R) 1-(1-{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyl}-piperidin-4-yi)-4-hydroxy-pyrrolidin-2-one; 262 2-(4-{2-[4-( 1 H-T etrazol-5-yi)~piperidin-1 -yl]-ethyi}-phenoxy)-benzothiazole; 263 (1-{2-[4-{Benzothiazo!-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yl)-methanol; 264 (1 -{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1 H-tetrazol-5-yl)-acetic acid ethyl ester; 265 (1 -{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyl}~1 H-tetrazol-5-yl)-acetic acid ethyl ester; 266 2-{4-[2-(5-Piperidin-4-yl-tetrazoi-2-yl)-ethoxy]-phenoxy}-benzothiazole hydrochloride; 267 7-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-spiro-[3-phthalidej-piperidine; 268 1-{3-[4-(Benzothiazol-2-yloxy)-phenyl]-propy[}-piperidine-4-carboxylic acid ethyl ester; 269 2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethy!amine hydrochloride; 544938 270 2-(4-{2~[4-(1H-Tetrazo]-5-yi)-piperidin-1-y]]-ethoxy}-phenoxy)-benzothiazole; 271 2-(4-Piperidiri-1 -ylmethyl-pherioxy)-benzooxazole; 272 [4-(Benzothiazol-2-yioxy)-benzyl]-cyclohexyi-eihy!-amine; 273 [4-(Benzothiazol-2-yloxy)-benzyi]-cyclopropylmethyl-propyl-amine; 274 1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxy!ic acid amide; 275 1 '-[4-(Benzothiazol-2-yloxy)-benzyi]-[1,4']bipiperidiriyl-2-one; 276 {4-[4-(Benzothiazol-2-yloxy)-berizyI]-piperazin-1-yi}-pyridin-3-yl-methanone; 277 {1-[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yimethyI}-carbamic acid tert-butyi ester; 278 {1-[4-(Benzothiazol-2-yloxy)-benzyi]-piperidin-4-ylmethyi}-carbamic acid methyl ester; 279 N-{C-[£4-(benzothiazol-2-yloxy)-benzyi]-piperidir>-4-yi]-methylamino sulfonyl}-carbamic acid tert-butyl ester, 280 N-{1-[4-(Benzothiazol-2-yloxy)-benzyi]~piperidin-4-yimethyl}-sulfamide hydrochloride, 281 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyi}-acetamide; 282 {1 -[4-{Benzothiazol-2-yloxy)-benzyl]-pipendir>4-yi}-acetic acicp 283 Acetic acid ({1-[4-(benzothiazol-2-y1oxy)-benzyI]-piperidin-4-ylmethyl}-carbamoyl)-methyl ester; 284 [2-{{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yimethyl}-carbamoyl)-cyclobutyl]-carbamic acid tert-butyl ester; 285 2-Amino-cyclobutariecarboxyiic acid {1-[4-(benzothiazol-2-yloxy)~ benzyl]-piperidin-4-ylmethyi}-amide dihydrochioride; 286 2-(4-Pyrrolidin-1 -ylmethyl-phenoxy)-benzothiazole; 287 2-{[4-(Benzothiazol-2-yIoxy)-benzyl]-ethyl-amino}-ethanol; 288 2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-2-yl}-ethanol; 289 1 -{4-[4-(Benzothiazol-2-yloxy)-benzy!]-piperazin-1 -y!}-ethanone; 290 8-[4-(Benzothiazol-2-yloxy)-benzyl]-2,8-diaza-spiro[4.5]decan-1-orie; 36 544938 291 Spiro[isobenzofuran-1(3H), 4'-piperidin]-3-one, 1'-[4-(Benzothiazol-2-yloxy)-benzyl] 292 {R)-1-[4~(Benzothiazol-2-yloxy)-benzyl]-pyrrolidin-3-ol; 293 2-[4-(2-Methyl-piperidin-1-ylmethyl)-phenoxy]-benzothiazoie; 294 [4-(Benzothiazol-2-yloxy)-benzyl]-diethyl-amine; 295 [4-(Benzothiazol-2-yloxy)-benzyl]-buty!-methyl-amine; 296 2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yI}-ethanoi; 297 1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ol; 298 {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-2-yl}-methanoi; 299 (R)-{1-[4-(Benzothiazol-2-yIoxy)-benzyl]-pyrrolidin-2-yl}-methanol; 300 2-(4-Azetidin-1-ylmethyl-phenoxy)-benzothiazole; 301 1-[4-(Benzothiazol-2-yloxy)-benzyl]-[1,4]diazepan-5-one; 302 {1-[4-(Benzothiazol-2-yloxy)-benzyi]-piperidin-3-yl}-methanol; 303 1 -[4-(Benzothiazo[-2-yloxy)-benzyl]-piperidine-3-carboxylic acid amide; 304 9-[4-(Benzothiazol-2-yloxy)-benzyl]-3,9-diaza-spiro[5.5]undecane-3-carboxyiic acid tert-butyl ester; 305 2-{1-[4-(Benzothiazol-2-yloxy)-benzyi]-piperidin-3-yl}-ethanol; 306 cis-4-{2-[4-{Benzothiazol-2-yloxy)-pheny!]-ethylamino}-cyclohexanecarboxylic acid trifluoromethanesulfonate salt; 307 (4-{2-[4-(Benzothiazol-2-y[oxy)-pheny!]-ethy!}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone; 308 Propane-2-suifonic acid (1-{2-[4-(benzothiazoI-2-yloxy)-phenoxyJ-ethyl}-piperidine-4-carbonyl)-amide; 309 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-oxo-acetic acid methyl ester; 310 N-(1 -{2-[4-(Benzothiazoi-2-yloxy)-phenyi]-ethy!}-piperidine-4-carbonyl)-benzenesulfonamide trifluoromethanesulfonate salt; 311 N-(1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidine-4~ carbonyl)-methanesulfonamide trifluoromethanesulfonate salt; 312 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperazin-1-yl)-oxo-acetic acid trifluoromethanesulfonate salt; 37 544938 313 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1 -yl)-morpholin-4-yl-methanone; 314 1 -(4-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperazin-1 -yl)-2-thiophen-2-yl-ethanone; 315 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-piperazin-1-yl)-pyridin-3-yl-methanone; 316 (4-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-piperazin-1-yl)-cyclopropyl-methanone; 317 1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-piperazin-1-yi)-2-methoxy-ethanone; 318 1-(4-{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperazin-1-yl)-2,2,2-trifluoro-ethanone; 319 4-(4-{2-[4-(Benzothiazol-2-yioxy)-pheny!]-ethyl}-piperazine-1 -carbonyl)-benzoic acid; 320 (4-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-piperazin-1-yl)-pyridin-4-yl-methanone; 321 (4-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethy(}-piperazin-1-yl)-(5-methyl-pyrazin-2-yl)-methanone; 322 {R)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone; 323 (S)-{4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethy!}-piperazin-1^yl)-{tetrahydro-furan-2-yl)-methartone; 324 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-(tetrahydro-furan-3-yl)~methanone; 325 1 -(4-{2-|4-(Benzothiazol-2-yIoxy)~pheny!]-ethyl}-piperazin-1 -yf)-2-hydroxy-ethanone; 326 2-[2-(4-{2-[4-(B enzoth iazo l-2-yioxy)-phe nyij-ethyl}-piperazi n-1 -yl )-2-oxo-ethyI]-cyclopentanone; 327 3-(4-{2-[4-{Benzothiazol~2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-propionic acid trifluoromethanesufonate salt; 328 3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yI)-oxazolidin-2-one; 38 544938 329 4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethy!}-piperidin-4-yl}-morpholin-3-one; 330 4-(1-{2-[4-(Benzothiazol-2-y!oxy)-phenoxy]-ethyl}-piperidin-4-yl)-morpholirv3-one; 331 3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl}-oxazolidin-2-one; 332 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-eihyI}-piperidine-4-carboxylic acid benzyloxy-amide; 333 (1 -{2~[4-{Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-yi)-acetic acid; 334 (ft)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-pheriyl]-ethyl}-piperidin-4-yi)-4-hydroxy-pyrrolidin-2-one; 335 1-{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidine-4-carboxylic acid hydroxyamide; 336 (S)-1-(1-{2-[4-(Benzothiazoi-2-yloxy)-phenyiJ-ethyi}-piperidii>4-yi)-4-hydroxy-pyrrolidin-2-one; 337 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-carbamic acid tert-butyl ester; 338 2-{4-[2-(4-Fluoro-piperidin~1-yl)-ethyl]-phenoxy}-benzothiazole; 339 2-{4-[2-(4,4-Difluoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazole; 340 (R)-1-{2-[4-(Benzothiazol-2-y!oxy)-phenyl]-ethyl}-pyrrolidin-3-ol; 341 N-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-yl)-formamide; 342 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-urea; 343 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-phenyl-isourea; 344 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-methyl-isothiourea; 345 N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-piperidin-4-yl)-methariesulfonamide; 346 1-(1-{2-[4-(Benzothiazol-2-yloxy)-pheriyl]-ethyl}-piperidin-4-yl)-3-cyano-2-methyl-guanidine; 39 544938 347 8-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-1-phenyl-1,3s8-triaza-spiro[4.5]decan-4-one; 348 8-{2-[4-(Benzothiazol-2-yloxy}-phenyl]-ethyi}-1,3)8-triaza-spiro[4.5]decane-2,4-dione; 349 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyI3-ethyl}-piperidin-4-yl)-methyl-carbamic acid tert-butyl ester; 350 N-(1-{2-[4-{Benzothiazoi-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-N-methyl-acetamide; 351 N-(1-{2-[4-(Benzothiazol-2-yIoxy)-phenyl]-ethy!}-piperidin-4~yI)-N-methyl-methanesulfonamide; 352 Acetic acid [(1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}~ piperidin-4-yl)-methyl-carbamoyl]-methyl ester; 353 N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-acetamide; 354 Acetic acid (1-{2-[4-(benzothiazoI-2-yioxy)-phenyl]-ethyl}-piperidin-4-ylcarbamoyl)-methyl ester; 355 2-({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-methyl-amino)-3-{1 H-imidazol-2-yl)-propionic acid; 356 2-(4-{2-[4-(3-Nitro-pyridin-2-yl)-[1,4]diazepan-1 -yl]-ethyl}-phenoxy)-benzothiazole; 357 2-(4-Pipendin-1-ylmethyl-phenoxy)-benzothiazole; j 358 1-[4-(Benzothiazol-2-yloxy)-benzyl]-4-phenyi-piperidin-4-ol; 359 1 -[4-(Berizothiazol-2~yloxy)-benzyl]-piperidin-4-ol; 360 {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methariol; 361 N-{1 -[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl}-methanesuifonarriide; i 362 N-{1-[4-{Benzothiazol-2-yloxy}-benzyl]-piperidin-4-ylmethyl}-2-hydroxy-acetamide; 363 {1 -[4-(Benzothiazo!-2-yloxy)-benzyl]-piperidir>4-yl}-carbamic acid methyl ester; 364 {1-[4-(Benzothiazoi-2-yloxy)-benzyl]-piperidin-4-ylrnethyi}-urea; 365 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yimethyi}-2,2,2-trif luoro-aceta m id e; 40 544938 366 {4-[4-{Benzothiazol-2-yloxy)-benzyi3-piperazin-1 -y!}-acetic acid; 367 2-[4-(4-Methanesulfonyl-piperazin-1 -y!methyi)-phenoxy]-benzothiazole; 368 1 -{4-[4-(Benzothiazol-2-yioxy)-benzyI]~piperazin-1 -yl}-2,2,2-trifluoro-ethanone; 369 2-(4-Morpholin-4-yimethyl-phenoxy)-benzothiazole; 370 {1 -[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl}-carbamic acid phenyl ester; 371 N-{1-[4-(Benzothiazol~2-yloxy)-benzyI]-piperidin-4-yl}-benzenesuifonamide; 372 3-[4-{Benzothiazol-2-yloxy)-benzylamino]-propionic acid ethyl ester; 373 3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propionic acid; 374 [(1-{2-[4-{Benzothiazol-2-yloxy)~phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl-amino]-acetic acid ethyl ester; 376 1 '-{2~[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy!}-[1,4']bipiperidinyl- 4-carboxylic acid ethyl ester; 377 1 ,-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4'Jbipiperidinyl-4-carboxylic acid; 378 {2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyciopropyl-ethyl-amine; 379 3-{{2~[4-(Benzothiazol-2-yloxy)-phenyi]~ethyi}-cyclopropyl-amino)-2-methyl-propionic acid trifluoromethansulfonic acid salt; 380 2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropylmethyl-amino)-ethanol; 381 2-[2-({2~[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethy(-amino)-ethoxy]-ethanol; 382 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-cyclopropylmethyl-amino)-propan-1-oi; 383 {2-[4-{Benzothiazof-2-yloxy)-phenyi]-ethyl}-cyciopropy!methyi-(3-tetrazol-2-yl-propyl)-amine; 384 {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-(3-pyrrol-1-yl-propyl)-amine; 41 544938 385 4-({2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethy(}-cyclopropylmethyl-amino)-butyronitrile; 386 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-piperidine-4-carboxylic acid (2-cyano-ethyt)-amide; 387 {2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-cyclopropylmethyi-j3-(2H-tetrazol-5-yl)-propyi]-amine; 388 3-[5-{1-{2-[4-(Benzothiazol-2-yloxy)-pheny]]-ethyi}-piperldin-4-y!)-tetrazol-1 -y!]-propionitrile; 389 {2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-cyclopropyl-[3-(2H-tetrazol-5-yl)-propyl]-amine; 390 1-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-piperidine-4-carboxylic acid (2-hydroxy-1!1-dimethyI-ethyl)-amide; 391 {2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyI}-cycIopropylmethyi-[3-(1 H-[1,2,4]triazol-3-yl)-propyl]-amine; 392 {2-[4-(Benzothiazo!-2-y!oxy)-phenyl]-ethyI}-cycIopropyImethyl-[3-(5-methyl-1 H-[1,2,4]triazol-3-yl)-propyl]-amine; 393 {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyimethyl-[3-(5-phenyl-1 H-[1,2,4]triazol-3-yl)-propyi]-amine; 394 2-(4-{2-[4-(1-MethyH H-tetrazoi-5-yI)-piperidin-1-y[]-ethyl}-phenoxy)-berizothiazole; 395 2-(4-{2-[4-{2-Methyl-2H-tetrazoi-5-yl)-piperidin-1 -yl]-ethyl}- ^ phenoxy)-benzoth iazole; 396 1-{2-[4-(BenzothiazoI-2-yloxy)-phenyS]-ethyl}-piperidine-4- i carbonitrile; 397 2-(4-{2-[4-(1 H-[1,2,3]TriazoI-4-yl)-piperidin-1-yI]-ethyI}-phenoxy)-benzothiazole; 398 4-{2-[4-(Benzothiazol-2-yloxy)-phenyl3-ethyiamino}-butyric acid ethyl ester; 399 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyi-amino)-butyric acid ethyl ester; 400 2-[3-({2-[4-(Benzothiazoi'-2-yIoxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-isoindole-1,3-dione; 42 544938 401 4-({2-[4-(Benzothiazol-2-y!oxy)-pheny[]-ethyl}-cyciopropyimethy!-amino)-butyric acid; 402 1-(3-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-propyi)-pyrrolidin-2-orie; 403 N-1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N1 -cyclopropylmethyl-propane-1,3-diamine; 404 5-{{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyclopropyl-amino)-pentarioic acid methyl ester; 405 N-[3-({2-[4-{Benzothiazol-2-yioxy)-phenyi]-ethy!}-cyclopropylmethyf-amino)-propyl]-acetamide; 406 Morpholine-4-carboxylic acid [3-{{2-[4-(benzothiazot-2-yloxy)-phenyl]-ethyI}-cyclopropylmethyl-amino)-propyl]-amide; 407 N-[3-({2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-methariesulfonamide 408 5-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyI}-cyclopropyl-amino)-pentanoic acid; 409 1-[3-({2-[4-(Benzothiazo!-2-yloxy)-pheny[]-ethyl}-isopropyl-amirio)-propyl]-pyrrolidin-2-orie; 410 1 -[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl>-cyclopropylmethyl-amino)-propyi]-pyrrolidin-2-one; 411 1 -[3-({2-[4-{Benzothiazol-2-yloxy)-pheny!j-ethyl}-cyciopropyl-amino)-propyl]-pyrrolidin-2-one; 412 1-[3-{{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-propyl-amino)-propyl]-pyrrolidin-2-one; 413 4-((1-Acetyl-piperidin-4-yl)-{2-[4-(benzothiazoI-2-y[oxy)-phenyl]-ethyl}-amino)-butyric acid ethyl ester; 414 4-((1-Acetyl-piperidin-4-yl)-{2-[4-(benzothiazo[-2-y!oxy)-phenyl]-ethy!}-amino)-butyric acid ethyl ester; 415 4-{{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-methanesulfonyi-amino)-butyric acid; 416 ({2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-cyc!opropyl~amino)-acetic acid; 43 544938 417 6-({2-[4-(Benzothiazol-2-y[oxy)-phenyl]-ethyl}-cyciopropyl-amino)-hexarioic acid ethyl ester; 418 7-({2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyclopropyi-amino)-heptanoic acid ethyl ester; 419 6-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyI-amino)-hexanoic acid; 420 7-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-heptarioic acid; 421 N-1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N 1 -cyciopropyl-proparie-1,3-diamine; 422 N-[3-({2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-cyclopropyl-amino)-propyl]-acetamide; 423 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-isobutyramide; 424 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-cyclopropyi-amino)-propyl]-benzamide; 425 N-[3-({2-[4-(Benzothiazoi-2-yloxy)-phenyi]-ethyl}-cyclopropyf-amino)-propyl]-4-chloro-benzamide; 426 N-[3-({2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-methanesulfonamide; 427 Propane-2-sulfonic acid [3-{{2-[4-{benzothiazol-2-yloxy)-phen^l]-ethyl}-cyclopropy]-amino)-propyl]-amide trifluoromethansulfonic acid salt; 428 8-({2-[4-(Benzothiazof-2-yioxy)-phenyl]-ethyl}-cyciopropyl-amino)-octanoic acid ethyl ester; 429 1-[3-({2-[4-(Benzothiazoi-2-yioxy)-phenyl]-ethyi}-cyclopropyi-amino)-propyl]-3-phenyi-urea; 430 8-{{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyi-amino)-octanoic acid; 431 Tetrahydro-furan-2~carboxylic acid [3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-amide; 432 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-2-hydroxy-acetamide; 44 544938 433 4-({2-[4-(Benzothiazol-2-y[oxy)-phenoxy]-ethyl}-cyclopropy!-amino)-butyric acid; 434 1-{3-[4-(Benzothiazol-2-yloxy)~benzyiamirio]-propyI}-pyrroIidirv2-one; 435 1-(3-{[4-(Benzothiazol-2-yioxy)-benzyi]-methyi-amino}-propyI)-pyrrolidin-2-orie; 436 1-(3-{[4-(Benzothiazol-2-yIoxy)-benzyI]-isopropyl-amino}-propyl)-pyrrolidin-2-one; 437 1-{3-{[4-(Benzothiazol-2-yIoxy)-benzyi]-ethyl-amino}-propyl)-pyrrolidin-2-one; 438 [4-(Benzothiazol-2-yloxy)-benzyl]-cyciopropy!-amine; 439 N-1-[4-{Benzothiazol-2-yloxy)-benzyl]-N1-cyclopropyl-propane-1,3-diamine; 440 N-(3-{[4-(Benzothiazol-2-yIoxy)-benzyl]-cyciopropyl-amino}-propyl )-isobutyram ide; 441 1-{3-{[4"(Benzothiazol-2-yioxy)-benzyi]-cyclopropyl-amino}-propyl)-3-isopropyl-urea; 442 1 -{1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-isopropyl-urea; 443 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yI}-oxaIarnic acid methyl ester; 444 N-{1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidiri-4-yI}-isobutyramide; 445 Tetrahydro-furan-2-carboxylic acid {1-[4-{benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide; 446 1 -{1 -[4-(Benzothiazol-2-yloxy)-benzy(]-piperidin-4-yi}-4-hydroxy-pyrrolidin-2-one; 447 1 -{1 -[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl}-4-hydroxy-pyrrolidin-2-one; 448 {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-y!}-urea; 449 N-{1-[4"(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-oxalamic acid; 45 544938 450 N-{1-[4-(Benzothiazol-2-yioxy)-benzyl]-piperidin-4-yi}-2-hydroxy-acetamide; 451 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-2,2,2-trifluoro-acetamide; 452 2-[4-(1,1 -Dioxo-1 l6-thiomorpholin-4-ylmethyl)-phenoxy]-benzothiazole; 453 N-{1 -[4-(benzothiazol-2-yloxy)-benzyI]-piperidin-4-amino sulfony!}-carbamic acid tert-butyl ester; 454 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-acetamide; 455 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N,N-dlmethylsulfamide; 456 1 -{1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-ethyI-urea; 457 1 -{1 -[4-(Benzothiazoi-2-yloxy)-benzyl]-piperidin-4-y!}-3-ethyl-thiourea; 458 Propane-1 -sulfonic acid {1 -[4-(benzothiazo!-2-yloxy)-benzyl]-piperidin-4-yl}-amide; 459 Propane-2-sulfonic acid {1 -[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide; 460 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-sulfamide; 461 N-{1-[4-(Benzothiazol-2-yloxy)-benzy!]-piperidin-4-yl}-formamide; 462 {1-[4-{Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic ^cid ethyl ester; 463 N-{1 -[4-(Benzothiazol-2-yioxy)-benzyl]-piperidin-4-yl}-propionamide; 464 N-{1-[4-(Benzothiazo[-2-yloxy)-benzyl]-piperidin-4~yi}-butyramide; 465 1 -{1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-y[}-3-propyl-urea; 466 {1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid propyl ester; 467 1-{1-[4-{Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-3-methyl-urea; 469 1 -{1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-1,3-dimethyl-urea; 46 544938 FCT/US2004/Q24309 470 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-1-methyl-urea; 471 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidirt-4-yI}-N-methyi-acetamide; 472 {1 -[4-(Benzothiazol-2-yloxy)-benzyi]-piperidin-4-yl}-methyl-carbamic acid methyl ester; 473 N-{1-[4-(Benzothiazol-2-yloxy)-benzyi]-piperidin-4-yI}-N-methyl-oxalamic acid methyl ester; 474 N-{1-[4-(Benzothiazol-2-yloxy)-benzyi]-piperidin-4-yi}-N-methyt-oxalamic acid; 475 Guanidine, N-{1-[4-{Benzothiazol-2-yIoxy)-benzyl]-piperidin-4-yl}-N'-hydroxy; 476 {1 -[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yi}-carbamic acid isopropyl ester; 477 3-{1 -[4~(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yI}-1,1 -dimethyl-urea; 478 Acetic acid {1-[4-(benzothiazol-2-yIoxy)-benzyi]-piperidin-4-ylcarbamoyl}-methyl ester; 479 {1-[4-(Benzothiazol-2-yloxy)-benzyi]-piperidin-4-y!}-thiourea; 482 2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzothiazole; and 483 2-[4-(2-Piperidin-1-yl-ethoxy}-phenoxy]-benzothiazole.
Additional embodiments of this invention, where X is NR5 with R5 being one of H and CH3, are made according to the synthetic methods outlined in Schemes A-C, F, G and J-L, have demonstrated LTA4H inhibitory activity, and are selected from the group consisting of: Example Compound 37 1 -{2-[4-( 1 /-/-Benzoimidazol-2-yloxy)-phenoxy]~etby!}-4-pbenyl-piperidin-4-ol; 38 {2-[4-(1H-Benzoimidazol-2-yioxy)-phenyi]-ethy!}-cyclopropylmethyi-propyl-amine; 47 544938 39 Cyclohexyl-ethyl-{2-[4-{1 -methy!-1 H-benzoimidazol-2-yloxy)-phenyl]-ethyl}-amine; 117 1 ~{2-[4-(1 H-Benzoirnidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol; 118 1 -{2-[4-{1H-BenzoimidazoI-2-yloxy)-phenoxy3-ethyl}-4-(4-chloro-phenyl)-piperidin-4-ol; 119 1 -{2-[4-(1 H-Benzoimidazo!-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol; 123 {2-[4-(1H-Benzoimidazol-2-yloxy)-phenyi]-ethyl}-cyciohexyi-ethyl-amine; 124 2-[4-{2-Pyrrolidin-1 -yl-ethyl)-phenoxy]-1 H-benzoimidazole; 125 2-[4-(2-Azepan-1 -yl-ethyl)-phenoxy]-1 H-benzoimidazole; 126 {2-[4-{1H-Benzoimidazol-2-yloxy)-phenyl]-ethyf}-dibutyi-amine; 127 1 -{2-[4-{1H-Benzoimidazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-ol; 128 1 ~{2-[4-(1 H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester; 129 {2-[4-(1H-Benzoimidazol-2-y!oxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine; 130 2-{4-[2-(4-Methyl-piperidin-1 -y!)-ethoxy]-phenoxy}-1 H-benzoimidazole; 131 2-{4-[2-(2-Ethyl~piperidin-1 -yl)-ethoxy]-phenoxy}-1 H~ j benzoimidazole; 132 2-[4-(2-Piperidin-1 -yl-ethoxy)-phenoxy]-1 H-benzoimidazole; 133 (1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-methanol; 134 1 -{2-f4-(1 H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol; 138 2-[4-(2-Azepan-1-yl-ethoxy)~phenoxy]-1 H-benzoimidazole amide; 139 {3-[4-(1 H-Benzoimidazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine; 140 2-[4-(2-Pyrrolidin-1 -yl-ethoxy)-phenoxy]-1 H-benzoimidazole; 141 {2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine; 142 2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-1 H-benzoimidazole; 230 2-[4-(2-Piperidin-1 -y!-ethyl)-phenoxy]-1 H-benzoimidazole; 48 544938 231 1 -(1 -{2-[4-(1 /-/-Benzoimidazol-2-yioxy)-phenoxy]-ethyt}-piperidin-4-yl)-pyrrolidin-2-one; 480 (1 -{2-[4-(1 H-Benzoimidazol-2-yIoxy)-phenoxy]-ethyI}-piperidin-4-yi)-methanol; and 485 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyI}-piperidine-4-carboxylic acid ethyl ester.
Compounds of the present invention may be prepared according to the reaction schemes described below. The schemes represent two basic approaches to target compound synthesis, both in a linear fashion, 5 commencing from either end of the molecule. Persons skilled in the art will recognize that certain compounds are more advantageously produced by one scheme over another.
To obtain the various compounds herein, starting materials may be employed which carry the ultimately desired substituents though the reaction 10 scheme with or without protection as appropriate. Starting materials may be obtained from commercial sources or synthesized by methods known to one skilled in the art. Alternatively, it may be necessary to employ, in the place of the ultimately desired substituent, a suitable group, which may be carried through the reaction scheme and replaced as appropriate with the desired 15 substituent. Any product containing a chiral center may be separated into its enantiomers by conventional techniques.
Embodiments of processes illustrated herein include, when chemically meaningful, one or more steps such as hydrolysis, halogenation, protection, and deprotection. These steps can be implemented in light of the teachings 20 provided herein and the ordinary skill in the art.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. In addition, compounds of the invention may be modified by using protecting groups; such compounds, 25 precursors, or prodrugs are also within the scope of the invention. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", ed, J.F.W. McOmie, Plenum 544938 Press, 1973; and T.W. Greene & P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd ed., John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Scheme A R2 N.
CI"^Mn "R; 3 o. ->• OH A2 >N r2 A1 A3 HO.
■O^H^Ra 2 if^i ?■ A4 N X^-0 filXX, R, „*=/ ~ ° n A6 Referring to Scheme A, n is 1 or 2 commercially available 4-benzyloxyphenol, A1, is alkylated with amino alkyl halides, A2; several amino alkyl chlorides are commercially available. The reactions can be run un^ier a 10 wide range of temperatures, including room temperature and more elevated temperatures, in the presence of an inorganic base known to facilitate O-alkylation, such as, but not limited to, K2C03, Cs2C03 and mixtures thereof (J. Med. Chem, 1997, 40, 1407-1416). Suitable solvents include but are not limited to DMF, Removal of the benzyl group on A3 may be accomplished 15 using catalytic hydrogenation conditions well known to those skilled in the art (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.). Suitable catalysts include but are not limited to Pd on carbon (Pd/C), in solvents such as ethyl acetate, alcohols and mixtures thereof. Examples of alcohols include but are not limited to CH3OH, 20 ethanol, /-PrOH. These reactions are typically run at room temperature. Removal of the benzyl group on A3 may be accomplished in some 50 544938 embodiments by using dissolving metal reductions or transfer hydrogenation conditions at suitable temperatures. For example, dissolving metal reductions are typically performed at temperatures below room temperature (-33 °C), Reaction of A4 with the aromatic bicyclic ring system, A5, suitably protected if 5 appropriate, may be accomplished within a wide range of temperatures including room temperature and more elevated temperatures in the presence of a suitable base including but not limited to amine or inorganic base as defined above. Suitable amine bases include but are not limited to triethylamine (TEA), A/,A/-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-10 7-ene (DBU), resin-bound amine bases and mixtures thereof. When X is oxygen or sulfur, protecting groups are not applicable. Suitable solvents include but are not limited to DMF, CH3CN, acetone and mixtures thereof. When X is NR5, and R5 is a suitable silicon based protecting group, such as SEM (trimethylsilylethoxymethyl), removal of the silicon-based protecting group 15 on NR5 can be accomplished using conditions well known to those skilled in the art (Greene et. al. as cited above). Typical reaction conditions include but are not limited to the use of tetrabutyiammoniurn fluoride (TBAF), in suitable solvents such as'THF at elevated temperatures. 51 544938 Scheme B A1 B2 B3 nr3 A3 HO i ^ ?2 •o-^H^R3 A4 A6 Referring to Scheme B, commercially available 4-benzyIoxyphenol, A1, is alkylated with dihaloalkanes, preferably dibromoalkanes such as 1,2-5 dibromoethane and 1,3-dibromopropane, B1, both of which are commercially available, under a wide range of temperatures with elevated temperatures preferred (Zhou, Z. -L. et al., J. Med. Chem. 1999, 42:2993-3000), Th^ reactions are conducted in the presence of an inorganic base known to facilitate O-alkylation such as, but not limited to, K2CO3, Cs2C03 and mixtures 10 thereof. Suitable solvents include but are not limited to CH3CN and DMF.
Compounds of structure B2 are treated with amines, B3, either in the presence or absence of a suitable amine base as described above under a wide range of temperatures with elevated temperatures preferred. Suitable solvents include CH3CN, CH2CI2 and DMF. Further conversion of the resulting products, of 15 structure A3, to compounds of structure A6, is as detailed above for Scheme A. 52 544938 Scheme C B2 HO HN^ B3 C1 HO 72 ■o-^M^r3 A4 A6 Referring to Scheme C, the benzyl group of compounds of structure B2 can be removed using catalytic hydrogenation conditions well known to those 5 skilled in the art (Greene et. al. as cited above). Suitable catalysts include but are not limited to Pd/C, in solvents such as THF and THF/ethanol mixtures. These reactions are typically run at room temperature. Removal of the benzyl group on B2 can be accomplished in some embodiments using transfer-hydrogenation conditions using suitable solvents and temperatures. 10 Compounds of general structure C1 are treated with amines of structure B3 either in the presence or absence of a suitable amine base as described above under a wide range of temperatures with elevated temperatures preferred. Suitable solvents include but are not limited to CHsCN, CH2CI2 and DMF. Further conversion of the resulting products, A4, to compounds A6, is as 15 detailed above for Scheme A.
Scheme D A5 C1 A6 1 ^ ^■o^H^R3 D1 53 544938 Referring to Scheme D, the compounds of structure A6 can also be prepared by treatment of compounds of structure C1 with aromatic bicyclic compounds, A5, where X = S and O, in the presence of a suitable inorganic base, as defined above, under a wide range of temperatures with elevated 5 temperatures preferred. Suitable solvents include but are not limited to DMF, CH3CN and mixtures thereof. Conversion of compounds of structure D1 to compounds of structure A6 can be accomplished by treatment with compounds of structure B3. These reactions can be performed either in the presence or absence of a suitable amine base as defined above or an inorganic base such 10 as, but not limited to, K2CO3, Cs2C03 and mixtures thereof as described above, under a wide range of temperatures with elevated temperatures preferred. Suitable solvents include but are not limited to CH3CN and DMF.
It is envisaged that when X is NR5, and R5 is a suitable silicon-based protecting group that the synthesis would follow that described above. The 15 removal of the silicon-based protecting group at the end of the synthetic sequence is further envisaged to occur using conditions as described by texts such as (Greene et. al. as cited above).
Scheme E E4 Referring to Scheme E, treatment of compounds of structure E1 with aromatic bicyclic compounds, A5, where X is Swhy not O also?, in the presence of a suitable inorganic base, as defined above, under a wide range of temperatures with elevated temperatures are preferred. Suitable solvents 54 544338 include but are not limited to DMF, CH3CN and mixtures thereof. Compounds of structure E2 can be converted to compounds of structure E3 using typical brominating conditions including but not limited to the use of PBra at elevated temperatures. Suitable solvents include but are not limited to benzene.
Compounds of structure E2 can also be converted to compounds of structure E4 using standard conditions for sulphonyiation well known to those skilled in the art. These include but are not limited to the use of TsCI to prepare tosylates, as denoted in the scheme, in the presence of an amine base at room temperature in CH2CJ2. Conversion of compounds of structure E3 to 10 compounds of structure E5 can be accomplished by treatment with compounds of structure B3. These reactions can be performed either in the presence or absence of a suitable amine base as described above or an inorganic base such as, but not limited to, K2CO3, CS2CO3 and mixtures thereof under a wide range of temperatures with elevated temperatures preferred. Suitable solvents 15 include but are not limited to CH3CN and DMF. Compounds of structure E4 can be converted to the compounds of the structure E5 by treatment with compounds of structure B3. These reactions can be performed either in the presence or absence of a suitable amine base as described above under a wide range of temperatures. Suitable solvents include but are not limited to 20 CH3CN and DMF.
It is envisaged that when X is NR5, and R5 is a suitable silicon-based protecting group that the synthesis would follow that described above. The removal of the silicon-based protecting group at the end of the synthetic sequence is further envisaged to occur using conditions as described by texts 25 such as Greene et. al. (as cited above). 55 544938 Scheme F HO HO n-OH n HAL B3 i E1 F1 Rz / A5 F3 Referring to Scheme F, commercially available 4-(2-hydroxy-ethyl)-phenol and 4-(2-hydroxy-propyl)~phenoi are converted to the corresponding 5 alkyl halides F1, where HAL is chloride or bromide, using typical brominating or chlorinating conditions. These conditions include but are not limited to treatment with 48% HBr solutions at elevated temperatures. The resulting bromophenols of structure F1 can then be treated with amines of the structure of B3 either in the presence or absence of a suitable amine base as described 10 above under a wide range of temperatures. Suitable solvents include but are not limited to CH3CN and DMF. Reaction of F2 with the aromatic bicyclic ring system, A5, suitably protected if appropriate, may be accomplished within a wide range of temperatures including room temperature and more elevated temperatures, in the presence of a suitable amine or inorganic base as defined 15 above. Suitable solvents include but are not limited to DMF, CH3CN, ac4tone and mixtures thereof. When X is O or S, protecting groups are not applicable. When X is NR5, and R5 is a suitable silicon-based protecting group, such as SEM (trimethylsilylethoxymethyl), removal of the silicon-based protecting group on NR5 can be accomplished using conditions well known to those skilled in the 20 art (Greene et. al. as cited above). Typical reaction conditions include but are not limited to the use of TBAF, in suitable solvents such as THF at elevated temperatures. 56 544938 Scheme G F3 Referring to Scheme G, G1, where n is 0 or 2 and HAL is bromide or chloride, are commercially available materials or may be obtained from **, and 5 G1, where n is 1, is envisaged to be available using standard alkylation conditions starting from 4-(2~hydroxy-ethyi)-pheno! and benzyl bromide. The benzyl group in G1 serves as a protecting group. Other compatible protecting groups known to one skilled in the art may be employed in this sequence. Compounds with the general structure G2 can be obtained by treatment with 10 amines of the general structure B3, either in the presence or absence of a suitable amine base as described above under a wide range of temperatures. Suitable solvents include but are not limited to CH3CN and DMF. Removal of the benzyl may be accomplished using catalytic hydrogenation conditions well known to those skilled in the art (Greene et. al. as cited above). Suitable 15 catalysts include but are not limited to Pd/C, in solvents such as ethyl acetate, alcohols and mixtures thereof. Examples of alcohols include but are not limited to CH3OH, ethanol, /-PrOH. These reactions are typically run at room temperature. Removal of the benzyl group on G2 may be accomplished in some embodiments using transfer-hydrogenation conditions at suitable 20 temperatures. Further conversion of the resulting products, F2, to the final target compounds F3 is as detailed above for Scheme F. 57 544938 Scheme H H3 OH R3 Referring to Scheme H, commercially available 4-benzyloxyphenol, A1, 5 is treated with epichlorohydrin, H1, both of which are commercially available. The reaction can be run under a wide range of temperatures, with elevated temperatures preferred, in the presence of an inorganic base such as, t^ut not limited to, K2C03, CS2CO3 and mixtures thereof. Suitable solvents include but are not limited to DMF. Conversion of compounds of structure H2 to 10 compounds of structure H3 can be accomplished by treatment with amines of general structure B3 either in the presence or absence of a suitable amine base as described above or an inorganic base such as, but not limited to, K2CO3, CS2CO3 and mixtures thereof under a wide range of temperatures with elevated temperatures preferred. Suitable solvents include but are not limited 15 to CH3CN and DMF. Removal of the benzyl group on H3 may be accomplished using catalytic-hydrogenation conditions well known to those skilled in the art (Greene et. al. as cited above). Suitable catalysts include but are not limited to Pd/C, in solvents such as ethyl acetate, alcohols and mixtures thereof. Examples of alcohols include but are not limited to ethanol, CHsOH, /- 58 544938 PrOH. These reactions are typically run at room temperature. Removal of the benzyl group on B2 can be accomplished in some embodiments using transfer-hydrogenation conditions using suitable solvents and temperatures.
Conversion of compounds of structure H4 to final target compounds H5 can be 5 accomplished by treatment with the aromatic bicyclic ring system, A5, where X is O, in the presence of a suitable inorganic base, as defined above, under a wide range of temperatures with lower temperatures preferred. Suitable solvents include but are not limited to acetone.
It is envisaged that when X is NR5, and R5 is a suitable silicon-based 10 protecting group that the synthesis would follow that described above. The removal of the silicon-based protecting group at the end of the synthetic sequence is further envisaged to occur using conditions as described by texts such as Greene et. al. {as cited above).
Scheme I 0C-"nx— 11 I2 13 81 I4 " 63 15 Referring to Scheme I, compounds of type 15 are prepared by heating commercially available 4-hydroxyphenyl acetic acid with, in the case of X is S, 2-aminothiophenol. In the case of X is O, 2-aminophenol is used. The two 20 starting materials are heated in the absence of solvent and the resulting phenols, 13, are treated with dihaloalkanes, preferably dibromoalkanes such as 1,2-dibromoethane and 1,3-dibromopropane, B1, both of which are commercially available, under a wide range of temperatures with elevated temperatures preferred (Zhou, Z. -L et at. as cited above). The reactions are 25 conducted in the presence of an inorganic base known to facilitate O-aikylation such as, but not limited to, K2CO3, CS2CO3 and mixtures thereof. Suitable solvents include but are not limited to CH3CN and DMF. Compounds of 59 544938 structure 14 are treated with amines, B3, either in the presence or absence of a suitable amine base as described above under a wide range of temperatures with elevated temperatures preferred. Suitable solvents include CHsCN, CH2CI2 and DMF.
Scheme J Referring to Scheme J, compounds of the structure J1 can be further elaborated within the limits of the claims to give more highly functionalized 10 target compounds. For example, hydrolysis using methods well known to those skilled in the art such as but not limited to the use of aqueous solutions of LiOH, KOH or NaOH, or aqueous solutions of HCI or CH3C02H, or the use of (CH3)aSiOK. Furthermore, persons skilled in the art will recognize that certain compounds are more advantageously produced by one method as 15 compared to another and that salts of the desired compounds may initially result. Compounds of the structure J2 can be further modified to give amides . using methods well known to those skilled in the art including but not limited to using (COCl2)2 to convert to the intermediary acid chloride followed by 60 544938 exposure to amines of the structure B3. Alternatively, standard amide bond-forming conditions may be utilized, including but not limited to the use of 1,(3-dimethyiaminopropy!)-3-ethylcarbodiimide (EDCI), with or without additives such as HOBT, and amines of the structure B3. Compounds of the structure 5 J4 can be further modified by reductive amination using standard conditions well known to those skilled in the art, including but not iimited to the use of an amine of the structure B3 and NaBH(OAc)3 in an appropriate solvent such as CH2CI2, CICH2CH2Ci or CF3CH2OH.
Scheme K K4 Referring to Scheme K, commercially available 3-fluoro-4-hydroxy- benzoic acid, K11, is converted to amides K2, with amines of structure B3, using standard peptide coupling conditions well known to those skilled in the 15 art such as, but not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1,3-dicyclohexyicarbodiimide (DCC), 0-(7-azabenzotriazol-l-ylJ-A/.A/.A/'A/-tetramethyluronium hexafluorophoshate (HATU), 0-benzotriazol-1-A/,A/,A/',A/'-tetramethy!uronium hexafluorophosphate (HBTU) and mixtures thereof. Suitable solvents include, but are not limited to, 20 CH2Cb and THF. The resulting amides of structure K2 are reduced to amines of formula K3 under reducing conditions well known to those skilled in the art, including but not limited to, lithium aluminum hydride in an appropriate solvent such as, but not limited to, THF. Conversion of benzyl amines K3 to the final target compounds, K4, can be accomplished by treatment with the aromatic 25 bicyclic ring system, A5, where X is S or O, in the presence of a suitable inorganic base under a wide range of temperatures with elevated temperatures 61 544938 preferred. Suitable inorganic bases include, but are not limited to, k2co3, CS2CO3 and mixtures thereof. Suitable solvents include, but are not limited to, acetone and CH3CN.
It is envisaged that when X is NR5, and R5 Is a suitable silicon-based 5 protecting group that the synthesis would follow that described above. The removal of the silicon-based protecting group at the end of the synthetic sequence is further envisaged to occur using conditions as described by texts such as Greene et. al. (as cited above).
Scheme L Referring to Scheme L, an alternate embodiment toward the preparation of compounds of formula (I) where n is 0 is described. The starting material L1, 4-hydroxybenzaldehyde, is converted to ethers of formula L2 by treatment with the aromatic bicyclic ring system, A5, where X is S or O, in the presence of 15 a suitable inorganic base under a wide range of temperatures with elevated temperatures preferred. Suitable inorganic bases include, but are not limited to, K2CO3, CS2CO3 and mixtures thereof. Suitable solvents include, but are not limited to, acetone and CH3CN. It is envisaged that when X Is NR5, and R5 is a suitable silicon-based protecting group that the synthesis would follow that 20 described above. The removal of the silicon-based protecting group at the end of the synthetic sequence is further envisaged to occur using conditions as described by texts such as Greene et. al. (as cited above). Aldehydes of formula L2 are converted to amines of formula L3 under reductive amination conditions with amines of formula B3. Suitable reducing agents include 25 Na(OAc)3BH and NaCNBH3, with or without the addition of activating agents such as acetic acid or ZnCla- Suitable solvents include THF and methanol, and 62 544938 reaction temperatures may range from 0 °C to 70 °C. Preferred reaction conditions are Na(OAc)sBH in THF at room temperature, Pharmaceutically acceptable salts, esters, and amides of compounds according to the present invention refer to those salt, ester, and amide forms of 5 the compounds of the present invention which would be apparent to the pharmaceuticai chemist, i.e., those which are non-toxic and which would favorably affect the pharmacokinetic properties of said compounds of the present invention. Those compounds having favorable pharmacokinetic properties would be apparent to the pharmaceutical chemist, i.e., those which 10 are non-toxic and which possess such pharmacokinetic properties to provide sufficient pafatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug, In addition, acceptable salts of carboxylates include sodium, potassium, calcium and magnesium. Examples of suitable cationic salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesuifonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmitic, 2-naphthaienesulfonic, p-toluenesulfonic, 20 cyclohexanesulfamic and saccharic.
More extensive sets of examples of acids and bases that may be used in the preparation of pharmaceutically acceptable salts include the following: Acids such as acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic 25 acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, 30 D-glucuronic acid, L-giutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DI_-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5- 63 544938 disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, 5 p-toluenesulfonic acid and undecylenic acid; and bases such as ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazoiet L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium 10 hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide. See, e.g., S.M. Berge, etal., "Pharmacetuical Salts", J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein by reference.
Examples of suitable esters include such esters where one or more 15 carboxyl substituents is replaced with p-methoxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, 9-anthryloxycarbonyl, CHaSChhCOO-, tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxycarbonyl, fur-2-yloxycarbonyl, benzoylmethoxycarbonyl, p-nitrobenzyioxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichioroethoxycarbonyl, 20 2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycar^ony!, 2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, or tetrahydropyran-2-yloxycarbonyl.
Compounds of the present invention may be used in pharmaceutical 25 compositions to treat patients (humans and other mammals) with disorders involving the action of the LTA4H enzyme. In particular, compounds of the present invention may be used in pharmaceutical compositions to treat inflammation. More particularly, compounds of the present invention may be used in pharmaceutical compositions to treat inflammatory conditions such as 30 inflammatory bowel disease (1BD) (such as Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease (COPD), arthritis, psoriasis, asthma, cystic fibrosis, atherosclerosis, rheumatoid arthritis, and multiple sclerosis. 64 544938 The present invention features pharmaceutical compositions containing such compounds and methods of using such compositions in the treatment or prevention of conditions that are mediated by LTA4H enzyme activity. Accordingly, the present invention also contemplates a pharmaceutical 5 composition that comprises at least one compound according to this invention, preferably dispersed in a pharmaceutically acceptable carrier. The at (east one compound according to this invention is present in such composition in an amount sufficient to inhibit LTA4H enzyme activity. More particularly, the at least one compound according to this invention is present in such composition 10 in an anti-inflammatory amount.
Accordingly, a pharmaceutical composition that comprises an antiinflammatory amount of at least one compound according to the present invention in a pharmaceutically acceptable carrier is also contemplated herein. The composition comprises a unit dosage of the at least one compound 15 according to this invention. In preferred practice, the at least one compound according to the present invention that is comprised in the pharmaceutical composition is capable of inhibiting LTA4H enzyme activity in the amount at which that compound is present in the pharmaceutical composition, when that pharmaceutical composition is introduced as a unit dose into an appropriate 20 patient or subject.
The terms "unit dose" and their grammatical equivalent forms are used herein to refer to physically discrete units suitable as unitary dosages for human patients and other animals, each unit containing a predetermined effective, pharmacologic amount of the active ingredient calculated to produce 25 the desired pharmacological effect. The specifications for the novel unit dosage forms of this invention are determined by, and are directly dependent on, the characteristics of the active ingredient, and on the limitations inherent in the art of compounding such an active ingredient for therapeutic use in humans and other animals.
The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques. Examples of suitable unit dosage forms are tablets, capsules, pills, powder packets, granules, wafers, and the like, segregated multiples of any unit dosage form, as well as 544938 liquid solutions, and suspensions. Oral dosage forms may be elixirs, syrups, capsules tablets and the like. Examples of solid carriers include those materials usually employed in the manufacture of pills or tablets, such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium 5 phosphate, mannitol and the like, thickeners such as tragacanth and methylcellulose USP, finely divided Si02) polyvinylpyrrolidone, magnesium stearate, and the like. Typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as needed with inert diluents (for example, sodium and calcium carbonates, sodium and calcium 10 phosphates, and lactose), disintegrants (for example, cornstarch and alginic acid), diluents, granulating agents, lubricants (for example, magnesium stearate, stearic acid, and talc), binders (for example, starch and gelatin), thickeners (for example, paraffin, waxes, and petrolatum), flavoring agents, coloring agents, preservatives, and the like by conventional techniques known 15 to those of ordinary skill in the art of preparing dosage forms. Coatings can be present and include, for example, glyceryl monostearate and/or glyceryl distearate. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules, in which the active ingredient is mixed with water or oil, such as peanut oil, liquid 20 paraffin, or olive oil.
Parenteral dosage forms may be prepared using water or anothej sterile carrier. For intramuscular, intraperitoneal, subcutaneous, and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. 25 Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, and gum tragacanth, and a wetting agent, such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate. 30 Physiologically acceptable carriers are well known in the art. Examples of liquid carriers are solutions in which compounds according to the present invention form solutions, emulsions, and dispersions. Compatible antioxidants, 66 544938 such as methlyparaben and propylparaben, can be present in solid and liquid compositions, as can sweeteners.
Pharmacetuical compositions according to the present invention may include suitable emulsifiers typically used in emulsion compositions. Such 5 emulsifiers are described in standard publications such as H.P. Fiedler, 1989, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetic und agrenzende Gebiete, Cantor ed., Aulendorf, Germany, and in Handbook of Pharmacetutical Excipients, 1986, American Pharmaceutical Association, Washington, DC, and the Pharmaceutical Society of Great Britain, London, UK, which are 10 incorporated herein by reference. Gelling agents may also be added to compositions according to this invention. Polyacrylic acid derivatives, such as carbomers, are examples of gelling agents, and more particularly, various types of carbopol, which are typically used in amounts from about 0.2% to about 2%. Suspensions may be prepared as a cream, an ointment, including a 15 water-free ointment, a water-in-oil emulsion, an oil-in-water emulsion, an emulsion gel, or a gel.
It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical administration, and 20 inhalation. For oral administration, the compounds of the invention will generally be provided in the form of tablets, capsules, or as a solution or suspension.
"Therapeutically effective amount" or "effective amount" and grammatically related terms mean that amount of active compound or 25 pharmaceutical agent that elicits the biological or medicinal response in a subject that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. "Subject" or "patient" includes mammals such as human beings and animals (e.g., dogs, cats, horses, rats, rabbits, mice, non-30 human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient or subject is a human being. 67 544938 Effective doses of the compounds of the present invention may be ascertained by conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition, the route of administration, and the weight of the patient. in general, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range from about 0.01 mg to about 1000 mg per day, more usually from about 1 mg to about 500 mg per day, and most usually form about 10 mg to about 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 10 about 0.0001 mg/kg and about 15 mg/kg, especially between about 0.01 mg/kg and about 7 mg/kg, and most especially between about 0.15 mg/kg and 2.5 mg/kg.
Anticipated oral dose ranges include from about 0.01 to 500 mg/kg, daily, more preferably from about 0.05 to about 100 mg/kg, taken in 1-4 15 separate doses. Some compounds of the invention may be orally dosed in the range of about 0.05 to about 50 mg/kg daily, while others may be dosed at 0.05 to about 20 mg/kg daily. Infusion doses can range from about 1.0 to about 1.0 x 104 pg/(kg.min) of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. For topical 20 administration, compounds of the present invention may be mixed with a pharmaceutical carrier at a concentration from about 0.1 to about 10% cdrug to vehicle.
A method for treating inflammation in a patient exhibiting or susceptible to an inflammatory condition is also contemplated. A method for treating an 25 LTA4H-mediated condition is also contemplated. The methods comprise administering to that patient an effective amount of a pharmaceutical composition that includes a unit dose of an active ingredient that is at least one of the compounds according to this invention dispersed in a pharmaceutically acceptable carrier.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also 68 544938 meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the 5 entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. 69 544938 EXAMPLES In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those skilled in the art may find other 5 methods of practicing the invention that are obvious to them. However, those methods are deemed to be within the scope of this invention.
General Experimental Procedures: NMR spectra were obtained on either a Bruker model DPX400 (400 10 MHz) or DPX500 (500 MHz) spectrometer. The format of the 1H NMR data below is: chemical shift in ppm down field of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).
Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in either positive or negative mode as indicated. 15 The "mass calculated" for a molecular formula is the monoisotopic mass of the compound.
Reversed-Phase HPLC retention times are reported in minutes, using the methods and conditions reported below.
Instrument: Gilson215 20 Solvent: CH3CN (0.05% trifluoroacetic acid, TFA)/H20 (0.05% TFA) Flow rate: 25 mL/min j Gradient: 0 min at 10% CH3CN; 20 min linear ramp to 99% CH3CN; Column: YMC-Pack ODS-A AA 12505-1530WT SH-362-5 (S-5 um, 12 nM, 150x30 mm) Temperature: 25 °C Wavelength: Dual detection at 220 and 254 nM Flash column chromatography was accomplished using ISCO Foxy 200 or ISCO OPTIX 10X systems employing one of the following commercially available prepacked columns: Biotage 40S (Si02 40 g), Biotage 40M (Si02 90 30 g), Biotage 40L (Si02 120 g), Biotage 65M (Si02 300 g) or ISCO Redisep (Si02, 10 g, 12 g, 35 g, 40 g, or 120 g). 70 544938 EXAMPLE 1 (h, Br 2-(4-Benzyloxy-phenoxy)-ethyl bromide.
To a stirring solution of 4-benzyioxyphenol (72 g, 359.6 mmol) in CH3CN (600 mL) was added dibromoethane (155 mL, 1.80 mol) and K2CO3 (105 g, 759.9 mmol). This brown suspension was heated at reflux and allowed to stir for 96 h. The resulting suspension was cooled to room temperature, diluted with acetone (250 mL), and filtered through diatomaceous earth, which was then 10 rinsed with additional acetone. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in CH3OH (500 mL), and the solution was stirred for 2 h. The title compound was obtained by filtration and air-dried to give 70 g (228 mmol, 63% yield) as a tan solid. 1H NMR (400 MHz, CDCI3): 7.60-7.30 (m, 5H), 6.88 (d, J = 8.4, 2H), 6.80 (d, J = 8.4, 2H), 4.70 (s, 2H), 3.79 15 (t, J = 5.8, 2H), 3.07 (t, J = 5.8, 2H).
EXAMPLE 2 To a stirring solution of 4-benzyloxyphenol (25 g, 124.9 mmoi) in CH3CN (125 mL) was added dibromopropane (63 mL, 624 mmol) and K2CO3 (34.5 g, 250 mmol). This brown suspension was heated at reflux and allowed to stir for 66 h. The suspension was then cooled to room temperature and filtered twice 25 through diatomaceous earth pads. The pads were rinsed with CH3CN, and the combined filtrates were concentrated under reduced pressure. The resultant oil was purified on SiC>2 (300 g; 33% CH2CI2/hexanes) to give 35.4 g (110 mmol, 88% yield) of a brown solid. 1H NMR (400 MHz, CDCI3): 7.46-7.29 (m, Br 1-[3-(4-Benzyloxy-phenoxy)-propyl]-bromide. 71 544938 5H), 6.85 (q, J = 8.1, 2H), 6.82 (q, J- 7.2, 2H), 5.03 (s, 2H), 4.06 (t, J =5.8, 2H), 3.61 (t, J = 6.5, 2H), 2.39 (m, J = 6.2, 2H).
EXAMPLE 3 4-(2-Bromo-ethoxy)-phenol. 2-(4-Benzyioxy-phenoxy)-ethyl bromide (EXAMPLE 1; 70 g, 227 mmol) was dissolved in THF (500 mL). To this solution was added Pd on carbon (10 wt %, 10 7 g) as a suspension in ethanol (50 mL). The resulting suspension was placed on a Parr hydrogenator at 40 psi of H2 and shaken overnight. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 48.5 g (224 mmol, 99% yield) of a tan solid. 1H NMR (400 MHz, CDCI3): 6.83 (d, J = 9.1, 2H), 6.77 (d, J = 9.1, 15 2H), 4.51 (s, 1H), 4.24 (t, J = 6.3, 2H), 3.62 (t, J = 6.3, 2H).
EXAMPLE 4 4-(3-Bromo-propoxy )-phenol. [3-(4-Benzyloxy-phenoxy)-propylj-bromide (10 g, 31.1 mmol) was dissolved in THF (100 mL). To this solution was added 10% palladium on carbon (1 g) as a suspension in THF (20 mL). The resulting suspension was placed on a Parr hydrogenator at 40 psi of H2, and shaken overnight. The reaction mixture was 25 filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 7 g (30.5 mmol, 98% yield) of a tan solid. 1H NMR: (400 MHz, CDCI3) 6.76 (d, J = 9.1, 2H), 6.69 (d, 9.1, 2H), 4.00 (t, J = 5.9, 2H), 3.60 (t, J = 6.6, 2H), 2.23 (m, J- 6.1, 2H). 72 544938 EXAMPLE 5 HO Br 4-(2-Bromo-ethyl)-phenol. 4-{2-Hydroxy-ethyl)-phenol (50 g, 362 mmol) was dissolved in 48 wt % HBr (250 mL). This light yellow solution was heated to 80 °C and stirred for 16 h. The reaction mixture was allowed to cool to room temperature and was then extracted with CH2CI2 (3 x 50 mL). The combined extracts were dried, filtered, and concentrated under reduced pressure to afford 72 g (100% crude yield) of 10 a tan solid. 1H NMR (400 MHz, CDCI3): 9.25 (s, 1H), 7.04 (d, J = 8.4, 2H), 6.67 (d, J = 8.4, 2H), 3.62 (t, J = 7.4, 2H), 2.97 (t, J = 7.4, 2H).
EXAMPLE 6 4-(3-bromo-propyl)-phenol.
A mixture of 4-(3-hydroxy-propyl)-phenol (52.7 g, 346.3 mmol) in 48 wt % HBr (265 mL) was stirred at 80 °C for 20 h and then cooled to room temperature. Water (400 mL) was added, and the product was extracted with CH2CI2 (500 20 mL). The extract was dried (MgSCU) and concentrated under reduced pressure to give the desired product as a beige solid (69 g, 92% yield). TLC (Si02, CH2CI2): Rf = 0.37. 1H NMR (400 MHz, DMSO-cfe): 9-18 (s, 1H), 6.99 (d, J = 8.3, 2H), 6.67 (d, J = 8.4, 2H), 3.47 (t, J = 6.6, 2H), 2.58 (t, J = 7.2, 2H), 2.05-1.95 (m, 2H).
EXAMPLE 7 2-Chloro-1-(2-trimethylsiianyl-ethoxymethyI)-1/-/-benzoimidazole. 73 544938 To a suspension of sodium hydride {6.2 g, 245 mmol) in DMF {275 mL) at 5 °C was added 2-chlorobenzimidazole (37 g, 243 mmol) via a solid-addition funnel over 30 min while maintaining the internal temperature of the mixture below 10 5 °C. An additional 25 mL of DMF was added, and the ice bath was removed. After 2 h, 2-(trimethylsiiyl)ethoxymethyi chloride (SEM-Cl) was added dropwise over 5 min. A white precipitate formed. The reaction mixture was stirred at room temperature for 18 h. To the mixture was added H20 (500 mL) and ethyl acetate (750 mL). The organic layer was washed with additional H2O (500 10 mL), dried (MgS04), and concentrated under reduced pressure, giving 65.8 g (96% yield) of the desired product as a clear golden oil, which solidified upon standing to give a beige solid. TLC (S1O2, 5% acetone/CH2CI2): Rf = 0.64. MS (ESI): mass calculated for C13H19CIN2OS1, 282.10; m/z found, 283.1. 1H NMR (400 MHz, CDCI3): 7.70 (d, J = 7.3, 1H), 7.46 (d, J = 7.6, 1H), 7.40-7.25 (m, 15 2H), 3.58 (t, J = 7.9, 2H), 0.92 (t, J = 8.3, 2H), 0.04 (s, 9H).
EXAMPLE 8 2-Chloro-1 -methyl-1 H-benzoimidazole. j Dimethyl sulfate (11.0 mL, 116 mmol) was added to a solution of 2-chlorobenzimidazole (10.6 g, 70 mmol) in 2.5 M NaOH (70 mL, 175 mmol), and the mixture was stirred at 23 °C for 2 h. The reaction mixture was filtered, and the solid product was washed with H20 (6 x 50 mL) and dried in vacuo to afford 25 a light brown solid (9.4 g, 81% yield). MS (ESI): mass calculated for CsHrCINs, 166.03; m/z found, 167.0 [M+Hf, 1H NMR (400 MHz, CDCi3): 7,75-7.70 (m, 1H), 7.35-7.29 (m, 3H), 3.82 (s, 3H). 74 544938 EXAMPLE 9 Br 2-[4-(2-Bromo-ethoxy)-phenoxy]-benzothiazole.
A solution of 4-(2-bromo-ethoxy)-phenoi (EXAMPLE 3; 8.7 g, 40.1 mmol) and 2-chlorobenzothiazoie (12 mL, 92 mmol) in CH3CN was treated with finely powdered CS2CO3 (26 g, 80 mmol), and the resulting mixture was stirred at 23 °C for 30 h, The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude solid was 10 purified on Si02 (100 g; 0-40% ethyl acetate/hexanes) to provide 6.7 g (47% yield) of a white solid. MS (ESI): mass calculated for C-isH-^BrNC^S, 348.98; m/z found, 350.0 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.78, (dd, J = 8.0, 0.4, 1H), 7.70 (dd, J = 8.0, 0.7, 1H), 7.42 (dt, J = 7.5, 1.3, 1H), 7.34 (dd, J = 9.1, 2H), 7.01 (dd, J- 9.1, 2H), 4.34 (t, J = 6.2, 2H), 3.70 (t, J= 6.2, 2H).
EXAMPLE 10 2-[4-(2-Bromo-ethyi)-phenoxy]-benzothiazoie.
A. 244-(Benzothiazol-2-vloxv')-phenvl]-ethanol. A solution of 4-hydroxyphenethyl alcohol (867 mg, 6.3 mmol) and 2-chlorobenzothiazoie 0.82 mL, 6.3 mmof) in CH3CN was treated with finely powdered Cs2C03 (4.1 g, 12.5 mmol), and the resulting suspension was stirred for 40 h at 70 °C. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to a crude oil, which was purified on Si02 (40 g; 0-50% ethyl acetate/hexanes) to provide 940 mg (55% yield) of a clear oil. MS (ESI): mass calculated for Ci5H13N02S, 271.07; m/z found, 272.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.78 (dd, J = 7.9, 0.4, 1H), 7.75 (dd, J = 7.9, 0.7, 1H), 7.46 (dt, J 75 544938 = 7.4, 1.3, 1H), 7.38-7.29 (m, 3H), 3.93 (q, J = 6.4, 2H), 2.94, (t, J = 6.5, 2H), 1.50 (m, 1H).
B. 2-[4-f2-Bromo-ethvl)-phenoxv'l-benzothiazoie. A solution of 2-[4-(benzothiazol-2~yloxy)-phenyl]-ethanol (174 mg, 0.64 mmol) in benzene (3 mL) 5 was treated with PBra (0.060 mL, 0.64 mmol), and the resulting suspension was heated to 70 °C for 90 min. The reaction mixture was cooled and diluted with ethyl acetate (30 mL). This solution was washed with H2O (10mL) then brine (10 mL), dried, and concentrated under reduced pressure. The crude product was purified on Si02 (12 g; 0-50% ethyl acetate/hexanes) to provide 10 120 mg of a light yellow oil. MS (ESI): mass calculated for CisH-^BrNOS, 332.98; m/z found, 335.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.79 (dd, J = 8.0, 0.3, 1H), 7.76 (dd, J = 8.0, 0.6, 1H), 7.42 (dt, J = 7.4, 1.2, 1H), 7.38-7.29 (m, 3H), 3.62 (t, J = 7.5, 2H), 3.25 (t, J =7.5, 2H).
EXAMPLE 11 2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-benzooxazole.
A. 1 -r2-(4-Benzvloxv-phenoxv)-ethvl1-piperidine. To a mixture of j 20 4-(benzyloxy)phenol (24.6 g, 123 mmol) and 1-(2-chioroethyl)piperidine hydrochloride (20.6 g, 112 mmol) in DMF (175 mL) was added K2CO3 (25 g,181 mmol) and Cs2C03 (40 g, 123 mmol). The reaction mixture was stirred for 3 days at room temperature. To the mixture was added H20 (300 mL) and CH2CI2. The organic layer was washed with 10% NaOH then brine, 25 dried (MgSCU), filtered, and concentrated under reduced pressure to give 33 g of a clear, dark purple liquid. The liquid was purified on Si02 (300 g; 0-50% ethyl acetate/hexanes) to give 23.4 g (67% yield) of a light yellow solid. TLC (Si02, 50% hexanes/ethyl acetate): Rf = 0.11. MS (ESI): mass calculated for C2oH25N02, 311.19; m/z found, 312.2 [M+Hf, 1H NMR (400 MHz, CDCig): 30 7.50-7.26 (m, 5H), 6.91 (d, J = 9.2, 2H,), 6.85 (d, J = 9.2, 2H), 5.02 (s, 2H), 76 544938 4.06 (t, J= 6.1, 2H), 2.76 (t, J= 6.1, 2H), 2.51 (brs, 4H), 1.65-1.55 (m, 4H), 1.45 (br s, 2H).
B. 4-(2-Piperidin-1 -vl-ethoxv Vohenol. To a solution of 1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine (15.0 g, 48.2 mmoi) in 1:1 ethanol/ethyl acetate (400 mL) was added Pd on carbon (10 wt %, 1.5 g). The mixture was placed on a Parr hydrogenator at 40 psi of H2for 20 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 9.4 g (88% yield) of the desired product as a light gray solid. TLC (Si02, 50% acetone/CbhCh): Rf = 0.16. MS (ESI): mass 10 calculated for Ci3H19N02, 221.14; m/z found, 222.1 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 8.88 (s, 1H), 6.73 (d, J = 6.6, 2H), 6.65 (d, J = 6.6, 2H), 3.93 (t, J = 6.0, 2H), 2.58 (t, J- 6.0, 2H), 2.40 (s, 4H), 1.51-1.45 (m, 4H), 1.35 (brs, 2H).
C. 2-f4-(2-Piperidin-1-vl-ethoxvVphenoxvl benzooxazoie. To a stirred solution 15 of 4-(2-piperidin-1-yl-ethoxy)-phenol (1.5 g, 6.8 mmol) in acetone (20 mL) at °C was added K2C03 (1.0 g, 7.2 mmol). To the mixture was added 2-chloro-benzooxazoie (0.5 mL, 4.4 mmol) at 5 °C. The resulting mixture was warmed to room termperature overnight. After 20 h the mixture was filtered, and the filtrate was concentrated under reduced pressure to a brown solid, which was 20 purified on Si02 (35 g; 50% acetone/CH2CI2). The desired fractions were combined and concentrated under reduced pressure to give 1.2 g (80% yield) of the desired product as a white solid. TLC (Si02! 50% acetone/CH2Cl2): Rf = 0.18. MS (ESI): mass calculated for C2gH22N203, 338.16; m/z found, 339.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.52 (d, J =7.2, 1H), 7.41 (d, J = 7.2, 1H), 25 7.35-7.20 (m, 4H), 6.97 (d, J = 9.1, 2H), 4.12 (t, J = 6.1, 2H), 2.79 (t, J = 6.0, 2H), 2.52 (s, 4H), 1.67-1.55 (m, 4H), 1.50-1.40 (m, 2H), EXAMPLE 12 {2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine. 77 544938 A. r2-(4-Ben2vloxv-phenoxv)-ethvll-diethvl-amine. To a mixture of 4-(benzyloxy)phenol (51 g, 255 mmol) and (2-chloro-ethyl)-diethyl-amine hydrochloride (41.6 g, 242 mmol) in DMF (400 mL) was added K2CO3 (37 g, 268 mmol) and CS2CO3 (87 g, 267 mmol). The reaction mixture was stirred at room temperature for 17 days. To the mixture was added H2O (600 mL) and CH2CI2. The organic layer was washed with H20, dried (MgSCU), filtered, and concentrated under reduced pressure to give 33 g of a clear, dark purple liquid, which was purified on Si02 (300 g; ethyl acetate) to give a light yellow oil (34.5 g, 48% yield). TLC (Si02, 50% hexanes/ethyl acetate): Rf=0.10. MS (ESI): 10 mass calculated for C19H25NO2, 299.19; m/z found, 300.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.50-7.28 (m, 5H), 6.89 (d, J = 9.2, 2H), 6.85 (d, J = 9.2, 2H), 5.02 (s, 2H), 4.00 (t, J = 6.4, 2H), 2.86 (t, J = 6.4, 2H), 2.63 (q, J = 7.2, 4H), 1.08 (t, J = 7.1, 6H).
B. 4-(2-Diethvlamino-ethoxv)-phenol. To a solution of [2-(4-benzyloxy-15 phenoxy)-ethyl]-diethyl-amine (21 g, 70 mmol) in 1:1 ethanol/ethyl acetate (500 mL) was added Pd on carbon (10 wt %, 1.5 g). The mixture was placed on a Parr hydrogenator at 40 psi of H2 for 20 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 13.1 g (89% yield) of the desired product as a clear 20 brown oil. MS (ESI): mass calculated for Ci2HigN02, 209.14; m/z found, 210.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 6.68 (s, 4H,), 3.99 (t, J = 6.2, 2H), 2.88 (t, J = 6.2, 2H), 2.69 (q, J = 7.2, 4H), 1.09 (t, J = 7.1, 6H).
C. -f2-r4-(6-Chloro-benzothiazol-2-vloxvyphenoxv1-ethvl)-diethvl-amine. To a solution of 4-(2-diethylamino-ethoxy)-phenol (500 mg, 2.39 mmol) in acetone (7 mL) containing CS2CO3 (876 mg, 2.69 mmol) was added 2,6-dichlorobenzthiazole (365 mg, 1.79 mmol). The mixture was heated at reflux for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a brown oil, which was purified on Si02 (35 g; acetone) to give 624 mg (76% yield) of the desired product. 30 TLC (Si02, acetone): Rf = 0.23. MS (ESI): mass found for Ci9H2iCIN202S, 376.10; m/z found, 377.1 [M+H]+. 1H NMR (400 MHz, CDC!3): 7.64 (d, J = 8.5, 2H), 7.34 (d, J = 8.8, 1H), 7.25 (d, J = 6.8, 2H), 6.96 (d, J- 9.1, 2H). 78 544938 EXAMPLE 13 (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]ethyI}-piperidin-4-yl)-methanol.
A, 4-f2-(4-Hvdroxvmethvl-piperidin-1 -vO-ethoxyl-phenol. A solution of 4-(2-bromo-ethoxy)-pheno! (EXAMPLE 3; 7 g, 32.2 mmol), piperidinemethanoi (5.2 g, 45.3 mmol), and A/,A/-diisopropylethylamine (7.9 mL, 45.3 mmol) in CH3CN (100 mL) was stirred at 65 °C for 18 h. The reaction mixture was cooled to room temperature and stirred an additional 48 h. The solvent was 10 removed under reduced pressure to yield a black semi-solid. This material was dissolved in CH2CI2 (200 mL), and the solution was washed with H20 (2 x 50 mL). The aqueous phase was back-extracted with 10% CH3OH/CH2CI2 (100 mL). The organic layers were combined, dried (Na2S04), filtered, and concentrated under reduced pressure to a black oil, which was purified on Si02 15 (120 g; 0-100% acetone/CH2CI2) to give the desired product as a brown oil. Diethyl ether was added to the oil to precipitate the product. Filtration yielded the title compound as a tan solid (1.9 g, 23% yield). TLQ (SiC>2, 5% 2 M NH3 in CH3OH/CH2CI2): Rf = 0.09. MS (ESI): mass calculated for C14H21NO3, 251.15; m/z found, 252.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 6.69 (st 4H), 20 4.03 (t, J = 5.9, 2H,), 3.51 (d, J = 6.5, 2H), 3.09 (d, J = 11.6, 2H), 2.79 (t, J = 5.9, 2H), 2.18-2.11 (m, 2H), 1.79 (d, J= 16.2, 2H), 1.49-1.62 (m, 1H), 1.36 (dq, J - 3.6, 12.3, 2H), 1.23 (brs, 2H).
B. (1 -f2-r4-Benzooxazol-2-loxvVphenoxv1ethvl}-piperidin-4-vl)-methanol. A mixture of 4-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-phenol (0.5 g, 1.98 25 mmol), 2-chloro-benzooxazole (205 |j,Lf 1.8 mmol) and CS2CO3 (1.35 g, 4.15 mmol) in acetone (8.0 mL) was stirred at room temperature for 48 h. The resulting mixture was filtered through diatomaceous earth, and the pad was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure to a yellow oil. The oil was purified on Si02 (40 g; 0-100% 30 acetone/CH2Ci2) to provide a solid, which was dissolved in CH2CI2 (100 mL). This solution was washed with 1 N NaOH (3x5 mL) then H20 (5 mL), dried 544938 (Na2S04), filtered, and concentrated under reduced pressure to yield the title compound as a white solid (424 mg, 64% yield). TLC (SiC^, 5% 2 M NH3 in CH3OH/CH2CI2): Rf = 0.17. MS (ESI): mass calculated for C21H24N2O4, 368.17; m/z found, 369.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.53-7.50 (m, 5 1H), 7.44-7.42 (m, 1H), 7.34-7.21 (m, 4H), 7.00-6.96 (m, 2H), 4.13 (t, J = 6.0, 2H,), 3.55-3.48 (m, 2H), 3.02-3.09 (m, 2H), 2.82 (t, J- 6.0, 2H), 2.13 (dt, J = 2.4, 11.8, 2H), 1.78-1.75 (m, 2H), 1.59-1.48 (m, 2H), 1.33 (dq, J = 3.7, 12.4, 2H).
EXAMPLE 14 1-{2~[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin~4-ol, A. 1-r2-(4-Hvdroxv-phenoxv)-ethvll-piperidin-4-ol. To a stirring solution of 4-(2-15 bromo-ethoxy)-phenol (EXAMPLE 3; 9 g, 42 mmol) in CH3CN (150 mL) was added 4-hydroxypiperidine (5.3 g, 52.5 mmol), followed by N,N-diisopropylethylamine (6.7 g, 52.5 mmol). The resulting solution was stirred overnight at room temperature, yielding a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure. Diethyl 20 ether was added to the resultant oil, and the mixture was warmed to 45 °C for 2 min, forming a white precipitate. This suspension was stirred at room temperature for 2 h, then filtered, giving 7.9 g (33 mmol, 79% yield) of an off-white solid. MS (ESI): mass calculated for C13H19NO3, 237.14; m/z found, 238.2 [M+Hf1. 1H NMR (400 MHz, CD3OD): 7.10 and 7.02 (q, J= 32.3, 9.0, 25 2H), 4.35 (t, J = 5.7, 2H), 3.59 (m, 1H), 3.26-3.19 (m, 2H), 3.07 (t, J = 5.7, 2H), 2.60 (t, J- 9.9, 2H), 2.20-2.12 (m, 2H), 1.94-1.82 (m, 2H).
B. 1-f2-r4-(Benzooxazol-2-vloxvVphenoxvVethvl>-piperidin-4-ol. To a stirring solution of 1-[2-(4-hydroxy-phenoxy)-ethyi]-piperidin-4-ol (500 mg, 2.1 mmol) in acetone (10 mL) was added CS2CO3 (1.4 g, 4.41 mmol). This suspension was cooled to 0 °C, and 2-chloro-benzooxazole (388 mg, 2.5 mmol, 0.29 mL) was added dropwise. The reaction mixture was allowed to warm to room 80 544938 temperature overnight, and was then filtered, and concentrated under reduced pressure. The resultant oil was purified on SiC>2(40 g; 0-100% acetone/CH2CI2) to give 400 mg (1.1 mmol, 54% yield) of a white solid. MS (ESI): mass calculated for C20H22N2O4, 354.16; m/z found, 355.2 [M+H]+1. 1H 5 NMR: (400 MHz, CDCI3) 7.55 (dd, J = 7.2, 1.8, 1H), 7.46 (dd, J = 7.3, 2.0, 1H), 7.36 (d, J = 9.1, 2H), 7.32-7.25 (m, 2H), 7.01 (d, J = 9.1, 2H), 4.18 (t, J = 5.4, 2H), 3.80 (m, 1H), 3.01-2.86 (m, 4H), 2.40 (br s, 1H), 1.99 (m, 2H), 1.74-1.65 (m, 2H), 1.48 (d, J = 4.1, 1H).
EXAMPLE 15 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol.
To a stirring solution of 1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidin-4-ol 15 (EXAMPLE 14, step A; 500 mg, 1.25 mmol) in DMF (10 mL), was added CS2CO3 (1.4 g, 4.41 mmol) and 2-chlorobenzothiazole (0.33 mL, 2.5 mmol). The suspension was heated to 80 °C and stirred overnight. The reaction mixture was allowed to cool to room temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, 20 and the residue was purified on Si02 (40 g; 0-100% acetone/CH2CI2), giving 321 mg (0.86 mmol, 69% yield) of a tan solid. MS (ESI): mass calculated for C20H22N2O3S, 370.14; m/z found, 371.2 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.64 (d, J = 8.0, 1H), 7.56 (d, J = 7.8, 1H), 7.30 (t, J = 7.2, 1H), 7.21-7.14 (m, 3H), 6.87 (d, J = 9.1, 2H), 4.05 (t, J = 5.8, 2H), 3.67 (br s, 1H), 2.82 (m, 2H), 25 2.76 (t, J = 5.8, 2H), 2.27 (t, J = 9.5, 2H), 2.01 (br s, 1H), 1.90-1.82 (m, 2H), 1.64-1.52 (m, 2H).
EXAMPLE 16 81 544938 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine.
A. 4-(2-Dibutvlamino-ethoxv)-phenol. To a stirring solution of 4-(2-bromo-ethoxyj-phenol (EXAMPLE 3; 8.2 g, 37 mmol) in CH3CN (150 mL), was added dibutylamine (5.98 g, 46.3 mmol) and A/,A/-diisopropylethyiamine (5.98 g, 46.3 mmol). The mixture was stirred overnight at 75 °C. The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure. The resultant oil was purified on Si02 (110 g; 0-100% acetone/CH2CI2) to give 7.7 g (29 mmol, 78% yield) of a brown solid. MS (ESi): mass calculated for 10 C16H27N02, 265.2; m/z found, 266.2 [M+Hf. 1H NMR (400 MHz, CDCl3): 6.81 (d, J = 7.0, 2H), 6.63 (d, J = 6.0, 2H), 4.22 (br s, 2H), 3.25 (br s, 2H), 2.93 (br s, 4H), 2.16 (brs, 2H), 1.88 (brs, 1H), 1.68 (brs, 4H), 1.33 (d, J = 5.7, 4H), 0.94 (br s, 6H).
B. f2-r4"(Benzooxazol-2-vloxvVphenoxv1-ethvl)-dibutvl-amine. To a stirring 15 solution of 4-(2-dibutylamino-ethoxy)-phenol (500 mg, 1.9 mmol) in acetone (9.4 mL) was added Cs2C03 (1.3 g, 3.9 mmol). This suspension was cooled to 0 °C, and 2-chloro-benzooxazole (346 mg, 2.2 mmol, 0.26 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight, then was filtered. The filtrate was concentrated under reduced 20 pressure. The resultant oil was dissolved in CH2CI2 and purified on Si02 (40 g; 0-100% acetone/CH2C!2) to give 180 mg (0.47 mmol, 25% yield) of a wj^ite solid. MS (ESI): mass calculated for C23H3oN203, 382.23; m/z found, 383.3 [M+Hf. 1H NMR (400 MHz, CDCIg): 7.50 (d, J = 7.2, 2H), 7.41 (d, J = 7.3, 2H), 7.31 (d, J= 9.1, 2H), 7.28-7.19 (m, 2H), 6.96 (d, J = 9.1, 2H), 4.13 (m, 25 2H), 2.88 (m, 2H), 2.54 (m, 4H), 1.47 (m, 4H), 1.32 (m, 4H), 0.92 (t, J = 7.3, 6H).
EXAMPLE 17 O 82 544938 1-{2-[4-(BenzothiazoI-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid ethyl ester.
A. 1-f2-(4-Hvdroxv-phenoxv)-ethvl1-piperidine-4-carboxviic acid ethyl ester. To 5 a stirring solution of 4-(2-bromo-ethoxy)-phenol (EXAMPLE 3; 5 g} 23.1 mmol) in CH3CN (200 mL) was added ethyl isonipecotate (5.3 mL, 34,7 mmol). The reaction mixture was heated to 84 °C and stirred for 16 h, then cooled to room temperature and concentrated under reduced pressure. The resultant oil was dissolved in CH2CI2 and purified on SiC>2 (300 g; 0-25% acetone/Ch^Cb) to 10 give a white solid (6.3 g, 93% yield). MS (ESI): mass calculated for C16H23N04, 293.16; m/z found, 294.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 6.63 (m, 4H), 4.07 (q, J = 7.2, 2H), 3.96 (t, J = 5.7, 2H), 2.96 (m, 2H), 2.74 (t, J = 5.6, 2H), 2.26-2.23 (m, 3H), 1.88-1.77 (m, 5H), 1.17 (t, J = 7,2, 3H).
B. 1 -f2-r4-(Benzothiazol-2-vloxv)-phenoxvl-ethvl)-piperidine-4-carboxvlic acid 15 ethvl ester. To a stirring solution of 1-[2-(4-hydroxy-phenoxy)-ethyl]-piperidine- 4-carboxylic acid ethyl ester (2.5 g, 6.8 mmol) in CH3CN (34 mL) was added CS2CO3 (5 g, 14.3 mmol) and 2-chlorobenzothiazole (1.26 mL, 10.2 mmol). The reaction mixture was heated to 75 °C for 3 h, then cooled to room temperature and filtered. The filtrate was concentrated under reduced 20 pressure. The residue was dissolved in CH2C!2 and purified on Si02 (40 g; 0-25% acetone/CHaCy to give a white solid (2.94 g, 100% yield). MS (ESI); mass calculated for C23H26N2O4S, 426,16; m/z found, 427.1 [M+H]4, 1H NMR (400 MHz, CDCI3): 7.76 (d, J = 8.0, 1H), 7.64 (t, J = 8.1, 1H), 7.41 (t, J = 8.4, 1H), 7.30 (d, J- 9.0, 3H), 7.05 (d, J= 6.8, 2H), 4,19 (t, J= 5.5, 2H), 4.12 (q, J 25 = 7.1, 2H), 3.02 (m, 2H), 2.83 (t, J = 5.5, 2H), 2,37 (m, 1H), 2.25 (t, J = 11.6, 2H), 1.93 (m, 2H), 1.79 (m, 2H), 1.24 (t, J = 7.2, 3H).
EXAMPLE 18 O 83 544938 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid potassium salt.
To a stirring solution of 1-{2-[4-(benzothiazoI-2-yloxy)-phenoxy]-ethyl}-5 piperidine-4-carboxylic acid ethyl ester (EXAMPLE 17; 235 mg, 0.5 mmol) in THF (2.5 mL) was added potassium trimethylsiianoate (282 mg, 2.2 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The resultant oil was dissolved in H2O, and the solution was treated to pH 9 with 1 M HCI. The resulting solution was 10 extracted with 1:3 isopropyl alcohol/chloroform (3 x 25 mL). The combined extracts were concentrated under reduced pressure to yield a tan solid that was triturated with diethyl ether. Filtration of the suspension afforded a tan solid (140 mg, 64% yield). MS (ESI): mass calculated for C2iH22N204S.(free acid), 398.13; m/z found, 399.1 [M+Hf. 1H NMR (400 MHz, DMSO-oTe): 8.01 15 (d, J = 7.3, 1H), 7.76 (d, J = 7.5, 1H), 7.51 (t, J = 8.4, 1H), 7.45 (d, J = 9.0, 2H), 7.40 (t, J = 7.2, 1H), 7.14 (d, J = 9.0, 2H), 4.18 (t, J = 5.5, 2H), 2.95 (m, 2H), 2.74 (t, J = 5.8, 2H), 2.10 (t, J = 10.5, 2H), 1.81 (m, 2H), 1.59 (m, 2H).
Example 19 (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperidin-4-yl)-pyrroIidin-1-yf-methanone.
To a suspension of 1-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperidine-4-25 carboxylic acid (EXAMPLE 18; 100 mg, 0.25 mmoi) in CHCl3 (2 mL) was added oxalyl chloride (132 jiL, 1.5 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The resultant solid was re-suspended in CHCI3 (2 mL), and pyrrolidine was added (100 fiL, 1.2 mmol). The solution that formed was stirred for 1 h and then was 30 diluted with CH2Ct2 (10 mL) and washed with sat. aq. NaHC03 (10 mL). The o / 544938 organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure to a yellow oil. The crude oil was purified on Si02 (10 g; 0-100% acetone/Ch^Ch) to provide the desired product as a colorless oil (71 mg, 63% yield). MS (ESI): mass calculated for C25H29N3O3S, 451.19; m/z found, 452.1 5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 7.6, 1H), 7.66 (dd, J = 8.0, 0.8, 1H), 7.41-7.37 (m, 1H), 7.29-7.24 (m, 3H), 6.99-6.96 (m, 2H), 4.13 (t, J = 6.0, 2H), 3.50-3.45 (m, 4H), 3.10-3.04 (m, 2H), 2.83 (t, J= 6,0, 2H), 2.38-2.31 (m, 1H), 2.21-2.14 (m, 2H), 1.98-1.84 (m, 6H), 1.74-1.71 (m, 2H).
Example 20 o o 3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperidine-4-carbonyi)-amino]-propionic acid ethyl ester. 1-Hydroxybenzotriazole hydrate (HOBT; 1.0 mL, 0.5 M in DMF, 0.5 mmol), 3-amino-proptonic acid ethyl ester (120 mg, 0.785 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI; 150 m, 0.785 mmol) were added in succession at 5 min intervals to a stirred suspension of 1-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid (EXAMPLE 18; 210 mg, 0.53 mmol) in CH2CI2 (3 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with CH2CI2 (10 mL) and washed with sat. aq. NaHCOs (10 mL) then H2O (10 mL). The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure to yield an off-white semi-solid. The crude residue was purified on Si02 (35 g; 0-5% 2 M NH3 in CH3OH/CH2CI2) to provide the desired product as a white solid (186 mg, 48% yield). MS (ESI): mass calculated for C26H31N3O5S, 497.20; m/z found, 498.4 [M+H]+, 1H NMR (400 MHz, CDCI3): 7.74 (dd, J = 8.1, 0.6, 1H), 7.66 (dd, J = 8.1, 0.8, 1H), 7.39 (dt, J = 7.4, 1.3, 1H), 7.29-7.24 (m, 3H), 7.01-6.94 (m, 2H), 6.18-6.15 (m, 1H), 4.19-4.11 (m, 85 544938 4H), 3.53 (q, J = 6.0, 2H), 3.06-3.04 (m, 2H), 2.81 (t, J = 5.9, 2H), 2.53 (t, J = 6.0, 2H), 2.18-2.06 (m, 3H), 1.88-1.72 (m, 4H), 1.28 (t, J = 7.2, 3H).
EXAMPLE 21 (1-{2-[4-(Benzooxazol-2-y[oxy)-phenoxyj-ethyI}-piperidin-2-y[)-methanol.
A. -f1-r2-(4-Benzvloxv-phenoxvVethvl1-piperidin-2-vl)-methanol. To a stirred solution of 2-(4-benzyloxy-phenoxy)-ethyi bromide (EXAMPLE 1; 7.0 g mg, 22.8 mmol) and piperidin-2-yl-methanol (3.3 g, 28.7 mmol) in CH3CN (100 mL) was added K2CO3 (7.1 g, 51.4 mmol). The mixture was heated at reflux for 20 h and then filtered. The filtrate was concentrated under reduced pressure to a clear golden oil, which was purified on Si02 (120 g; 0-100% acetone/CH2CI2) to give 6.0 g (77% yield) of a white solid. TLC (Si02, 15 acetone): Rf = 0.15. MS (ESI): mass calculated for C21H27NO3, 341.20; m/z found, 342.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe); 7.48-7.25 (m, 5H), 6.92 (d, J - 9.1, 2H), 6.85 (d, J = 9.1, 2H), 5.02 (s, 2H), 4.38 (t, J = 5.3, 2H), 3.96 (t, J = 6.2, 2H), 3.55-3.48 (m, 1H), 3.43-3.32 (m, 1H), 3.15-3.00 (m, 1H), 2.88-2.85 (m, 1H), 2.75-2.62 (m, 1H), 2.30-2.22 (m, 2H), 1.61 (d, J = 9.4, 2h{ 1.52-20 1.44 (m, 1H), 1.44-1.31 (m, 1H), 1.30-1.17 (m, 2H).
B. 4-r2-f2-Hvdroxvmethvl-piperidin-1 -vD-ethoxvl-phenol. To a solution of {1-[2-(4-benzy!oxy-phenoxy)-ethyl]-piperidin-2-yl}-methanoI (6.0 g, 17.6 mmol) in 1:1 ethanol/ethyl acetate (75 mL) was added Pd on carbon (10 wt %, 614 mg). The mixture was placed on a Parr hydrogenator at 40 psi of H2for 20 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 4.5 g (100% yield) of the desired product as a clear and colorless oil. TLC (Si02, acetone): Rf = 0.29. MS (ESI): mass calculated for C-i4H2iN03f 251.15; m/z found, 252.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 6.77 (d, J = 6.6, 2H), 6.68 (d, J = 6.6, 2H), 4.06-4.01 86 544938 (m, 2H), 3.70-3.55 (m, 2H), 3.22-3.10 (m, 1H), 3.05-2.96 (m, 1H), 2.88-2,79 (m, 1H), 2.47-2.36 (m, 2H), 1.76-1.70 (m, 2H), 1.63-1,32 (m, 4H). C. (1 -(2-f4-(Benzooxazol-2-vloxvVphenoxv1-ethvl)-piperidin-2-vn-methanoi. A mixture of 4-[2-(2-hydroxymethy!-piperidin-1-yi)-ethoxy]-phenol (197 mg, 0.78 5 mmol), 2-chloro-benzooxazole (116 \iL, 1,02 mmol) and CS2CO3 (700 mg, 2.15 mmol) in acetone (10 mL) was stirred at room temperature for 20 h. The resulting mixture was filtered through diatomaceous earth. The pad was washed with acetone, and the combined filtrates were concentrated under reduced pressure to a golden oil. The oil was purified on SiC>2 (10 g; 0-100% 10 acetone/CH2Cl2) to give the desired product as a clear and colorless oil (202 mg, 70%). TLC (Si02l acetone): Rf = 0,17. MS (ESI): mass calculated for C21H24N203SI 384.15; m/z found, 369.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6)\ 7.61 (d, J = 7.0, 2H), 7.50 (d, J = 7.0, 2H), 7.41 (d, J = 9.1, 4H), 7.35-7.30 (m, 4H), 7.03 (d, J = 9.1, 4H,), 4.41 (t, J = 5.3, 2H), 4.07 (t, J = 6,2, 4H), 3.60-15 3.52 (m, 2H), 3.44-3.35 (m, 2H), 3.18-3.08 (m, 2H), 2.90-2.85 (m, 2H), 2.78-2.72 (m, 2H), 2.35-2.28 (m, 4H), 1.62 (d, J= 9.2, 4H), 1.53-1.47 (m, 2H), 1.47-1.34 (m, 2H), 1.32-1.18 (m, 4H).
EXAMPLE 22 o 1_{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid amide.
A suspension of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (EXAMPLE 9; 25 200 mg, 0.57 mmol), isonipecotamide (73 mg, 0.57 mmol) and Siiicycle® dimethylamine resin (800 mg, 1.14 mmol) in CH3CN was heated to 70 °C for 18 h. The reaction mixture was filtered, and the collected resin was rinsed with CH3CN. The combined filtrates were concentrated under reduced pressure yielding a crude solid, which was purified on Si(?2 (10 g; 0-100% 10% [2 M 30 NH3 in CH3OH] in CH2CI2/CH2CI2) to provide 142 mg (63% yield) of a white 87 544938 solid. MS (ESI): mass calculated for C2iH23N3C>3St 397.15; m/z found, 398.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.85 (dd, J=8.0, 0.3, 1H), 7.75 (dd, J =8.0, 0.6, 1H), 7.42 (dd, J=7.4, 1.1, 1H), 7.32-7.22 (m, 3H), 7.02-6.91 (m, 2H), 5.67 (br d, J =47, 2H), 4.15 (t, J = 5.8, 2H), 3.09 (br d, J =8.8, 2H)t 2.85 (t, J 5 =5.7, 2H), 2.28-2.12 (m, 3H), 2.00-1.88 (m, 2H), 1.87-1.72 (m, 2H).
EXAMPLE 23 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrrolidin-2-one A suspension of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazoIe (EXAMPLE 9; 200 mg, 0.57 mmol), 1-piperidin-4-yl-pyrrolidin-2-one hydrochloride (117 mg, 0.57 mmol), and Silicycle® dimethylamine resin (800 mg, 1.14 mmol) in CH3CN was heated to 70 °C for 18 h. The reaction mixture was filtered, and the 15 collected resin was rinsed with CH3CN. The combined filtrates were concentrated under reduced pressure yielding a crude solid, which was purified on Si02 (10 g; 0-100% 10% [2 M NH3 in CH3OH] in CH2CI2/CH2CI2) to provide a tacky off-white solid (142 mg, 63% yield). MS (ESI): mass calculated for C24H27N303S, 337.18; m/z found, 348.5 [M+H]+. 1H NMR (400 MHz, C^CI3): 20 7.85 (dd, J= 8.0, 0.5, 1H), 7.75 (dd, J= 8.0, 0.8, 1H), 7.41 (dt, J = 7.3, 1.5, 1H), 7.34-7.22 (m, 3H), 7.02-6.92 (m, 2H), 4.15 (brd, J = 48.8, 2H), 3.80-3.65 (m, 1H), 3.40 (t, J = 7.0, 1H), 3.30-3.10 (brs, 1H), 3.15, (q, J = 7.2, 1H), 2.96{brs, 1H), 2.42, (t, J= 7.9, 2H), 2.10-1.99 (m, 1H), 1.81-1.70 (m, 1H) 1.68-1.52 (m, 4H), 1.50 (d, J = 6.5, 3H).
EXAMPLE 24 88 544938 1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethylH1,4']bipiperidinyi-2-one.
To a stirred solution of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (EXAMPLE 9; 542 mg, 1.55 mmol) and [1,4']bipiperidinyI-2-one hydrochloride 5 (371 mg, 1.69 mmol) in CH3CN (20 mL) was added K2C03 (517 mg, 3.74 mmol). The mixture was heated at reflux for 20 h and then was filtered. The filtrate was concentrated under reduced pressure to a clear golden oil, which was purified on Si02 (10 g; 0-100% acetone/CH2CI2) to give 294 mg (42% yield) of a white solid. TLC (Si02, acetone): Rf = 0.15. MS (ESI): mass 10 calculated for C25H29N303S, 451.19; m/z found, 452.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.92 (d, J = 1.1, 2H), 7.90 (d, J = 1.1, 2H), 7.42 (t, J = 7.3, 2H), 7.37 (d, J = 9.0, 2H), 7.31 (t, J = 7.3 2H), 7.06 (d, J = 9.0, 2H), 4.32-4.21 (m, 1H), 4.10 (t, J = 5.7, 2H), 3.15 (t., J = 5.3, 2H), 3.00 (d, J = 11.5, 2H), 2.71 (t, J = 5.7, 2H), 2.21 (t, J = 6.5, 2H), 2.10 (t, J = 11.4, 2H), 1.75-1.58 (m, 6H), 15 1.43 (d, J= 10.0, 2H).
EXAMPLE 25 8-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,8-diaza~spiro[4,5]decan/-1-one.
A suspension of 2-[4-(2-bromo~ethoxy)-phenoxy]-benzothiazole (EXAMPLE 9; 257 mg, 0.73 mmol), 2,8-diaza-spiro[4.5]decan-1-one hydrochloride (153 mg, 0.80 mmo!) and Silicycle® dimethylamine resin (1.7 g, 2.4 mmol) in CH3CN was heated to 80 °C for 18 h. The reaction mixture was filtered, and the collected 25 resin was rinsed with CH3CN. The combined filtrates were concentrated under reduced pressure to a crude solid, which was purified on Si02 (10 g; 0-100% 10% [2 M NH3 in CH3OH] in CH2Cl2/CH2Ci2) to provide an off-white solid (152 mg, 49% yield). MS (ESI): mass calculated for C23H25N303S, 423.16; m/z found, 424.2 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.78 (dd, J = 8.1, 0.6, 1H), 30 7.69 (dd, J = 8.0, 0.8, 1H), 7.41 (dt, J = 7,5, 1.3, 1H), 7.32-7,27 (m, 3H), 7,00 89 544938 (m, 2H), 6.36 (br s, 1H), 4.15 (t, J = 5.9, 2H), 3.36 (t, J = 7.0, 2H), 3.00, (dt, J = 11.9, 3.9, 2H), 2.87 (t, J = 5.8, 2H), 2.32 (dt, J= 11.5, 2.4, 2H), 2.10-1.98 (m, 2H), 2.07 (t, J = 7.0, 2H), 1.50 (br d, J = 13.3, 2H).
EXAMPLE 26 2-[4-(3-Pyrrolidin-1~yl-propoxy)-phenoxy]-benzothiazole.
A. 1 -f3-(4-Benzvloxv-phenoxvVpropvn-Pvrrolidine. To a mixture of 1-[3-(4-10 benzy!oxy-phenoxy)-propyl]-bromide (EXAMPLE 2; 1.50 g, 4.7 mmol) was added pyrrolidine (2.0 mL, 24.0 mmol) in CH3CN. The mixture was stirred for 20 h then concentrated under reduced pressure to give a yellow oil, which was purified on Si02 (35 g; acetone) to give 1.2 g (80% yield) of the desired product as a white solid. TLC (Si02l acetone): Rf = 0.05. MS (ESI): mass calculated 15 for C2oH25N02, 311.19; m/z found, 312.2 [M+H]+. 1H NMR (400 MHz, CDC!3): 7.50-7.30 (m, 5H), 6.90 (d, J = 9.1, 2H), 6.82 (d, J = 9.1, 2H), 5.02 (s, 2H), 4.00 (t, J = 6.1, 2H), 3.0-2.75 (m, 6H), 2.15 (d, J = 6.2, 2H), 1.94 (br s, 4H).
B. 4-(3-Pvrrolidin-1 -vl-propoxy)~phenol. To a solution of 1 -[3-(4-benzyloxy-phenoxy)-propyl]-pyrrolidine (1.2 g, 3.9 mmol) in 1:1 ethanol/ethyl acetate (65 mL) was added Pd on carbon (10 wt %, 206 mg). The mixture was placed on a Parr hydrogenator at 40 psi of H2 for 20 h. The resultant mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 875 mg (100% yield) of the desired product as a brown solid. MS (ESI): mass calculated for C-i3H-i9N02, 221.14; m/z found, 25 222.2 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 8.90 (s, 1H), 6.74 (d, J = 9.0, 2H), 6.65 (d, J = 9.0, 2H), 3.90 (t, J = 6.3, 2H), 2.72 (br s, 6H), 1.90 (quint, J = 7.4, 2H), 1.76 (s, 4H).
C. 2-r4-(3-Pvrrolidin-1 -vl-propoxvVphenoxvl-benzothiazole. To a stirred solution of 4-(3-pyrrolidin-1-yl-propoxy)-phenol (100 mg, 0.45 mmol) in acetone (5 mL) containing Cs2C03 (213 mg, 0.65 mmol) was added 90 544938 2-chlorobenzthiazole (65 }iL, 0.50 mmol): The mixture was heated at reflux for 24 h and then filtered. The filtrate was concentrated under reduced pressure to give a clear golden oil, which was purified on SiOa (10 g; acetone) to give 97 mg (61% yield) of the desired product. TLC (SiOa, acetone): Rf = 0,02. MS 5 (ESI): mass calculated for C20H22N2O2S, 354.14; m/z found, 355.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.73 (d, 1H), 6.95 (d, 1H), 7.39 (m, 1H), 7.26 (m, 3H), 6.96 (d, J = 9.1, 2H), 4.06 (t, J = 6.4, 2H), 2.65 (t, J = 7.3, 2H), 2.55 (br s, 4H), 2.04 (quint, J = 6.5, 2H), 1.82 (br s, 4H).
EXAMPLE 27 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-phenyl-piperidin-4-oI.
A. 1-r3-f4-Hvdroxv-phenoxvVpropyH-4-phenvl-piperidin-4-ol hydrogen bromide. 4-(3-Bromo-propoxy)-phenol (EXAMPLE 4; 3 g, 13 mmol) was dissolved in CH3CN (65 mL). To this solution was added 4-hydroxy-4-phenylpiperidine (6.8 g, 39 mmol), and the mixture was stirred at room temperature oversight, yielding a white precipitate. The suspension was filtered to give the title compound as a white solid (5 g, 11.9 mmol, 91% yield). MS (ESI): mass calculated for C20H25NO3 (free base), 327.18; m/z found, 328.2 [M+H]+, 1H NMR (400 MHz, CD3OD): 7.49 (d, J = 7.5, 2H), 7.32 (t, J = 7.5, 2H), 7.21 (t, J =7.2, 1H), 6.73 (q, J = 12.3, 4H), 3.96 (t, J = 6.1, 2H)f 2.85 (d, J = 11.3, 2H), 2.64-2.54 (m, 4H), 2.13 (dt, J = 9.0, 3.9, 2H), 2.00 (m, 2H), 1.75 (d ,J= 12.2, 2H).
B. 1-(3-r4-(Benzooxazol-2-vioxvVphenoxv1-propvlM-phenvl-piperidin-4-ol. To a stirring solution of 1-[3-(4-hydroxy-phenoxy)-propyl]-4-phenyl-piperidin-4-ol hydrogen bromide (500 mg, 1.5 mmol) in acetone (7 mL) was added CS2CO3 (1.03 g, 3.15 mmol). This suspension was cooled to 0 °C, and 2-chioro-benzooxazole (276 mg, 1.8 mmol, 0.2 mL) was added dropwise. The reaction 91 544938 mixture was allowed to warm to room temperature overnight, then filtered and concentrated under reduced pressure. The resultant oil was dissolved in CH2CI2 and purified on Si02{40 g; 0-100% acetone/CH2CI2) to give 450 mg (1.05 mmol, 70% yield) of a white solid, MS (ESI): mass calculated for 5 C26H2eN204r 444.20; m/z found, 445.20 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.47-7.43 (m, 3H), 7.36-7.11 (m, 8H), 6.90 (d, J- 9,1, 2H), 3.99 (t, J= 5.8, 2H), 2.80 (d, J= 9.5, 2H), 2.56 (t, J= 6.8 Hz, 2H), 2.44 (t, J= 10.9, 2H), 2.13 (t, J-11.0, 2H), 1.98 (m, J = 6.8, 2H), 1.71 (d, J = 6.9, 2H).
EXAMPLE 28 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-benzyl-piperidin-4-ol.
A. 4-Benzvl-1 -[3-(4-hvdroxv-phenoxvVpropvn-piperidin-4-ol. 4-Benzyi-4-15 hydroxy-piperidine (750 mg, 3.9 mmol) was added to a solution of 4-(3-bromo-propoxy)-phenol (EXAMPLE 4; 300 mg, 1.31 mmol) in CH3CN (6 mL), The reaction mixture was stirred at room temperature overnight, yielding a white precipitate. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The resultant oil was purified on Si02 (10 g; 0^-100% 20 acetone/CH2CI2) to give 110 mg (0.32 mmol, 25% yield) of a white solid. MS (ESI): mass calculated for C2iH22N03, 341.20; m/z found, 342.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.36-7.24 (m, 3H), 7.22 (d, J = 6.9, 2H), 6.7 (m, 4H), 4.07 (t, J = 6.5, 2H), 3.41 (d, J = 11.7, 2H), 3.19 (t, J = 7.8, 2H), 3.11 (t, J = 11.8, 4H), 2.84 (brs, 2H), 2.34 (brs, 4H), 2.18 (brs, 1H), 1.72 (d, 14.5, 2H). 25 B. 1-{3-[4-(Benzooxazol-2-vloxv)-phenoxv1-propvlM-benzvl-piperidin-4-ol. To a stirring solution of 4-benzyl-1-[3-(4-hydroxy-phenoxy)-propyi]-piperidin-4-oi (2.5 g, 7.3 mmol) in acetone (37 mL) was added CS2CO3 (4.99 g, 15.3 mmol). This suspension was cooled to 0 °C, and 2-chloro-benzooxazoie (1.1 mL, 9.5 mmol) was added dropwise. The reaction mixture was allowed to warm to 30 room temperature overnight, was filtered and then was concentrated under 92 544938 reduced pressure. The resultant oil was dissolved in CH2C12 and purified on Si02 (110 g; 0-100% acetone/CHaCb) to give 310 mg {0.67 mmol, 9% yield) of a white solid. MS (ESI): mass calculated for C28H30N2O4, 458.2; m/z found, 459.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.49 (d, J= 7.2, 1H), 7.41 (d, J = 5 7.2, 1H), 7.35-7.18 (m, 9H), 6.94 EXAMPLE 29 2-[4-(2-Piperidin-1 -yl-ethyl)-phenoxy]-benzooxazo!e.
A. 4-(2-Piperidin-1 -vl-ethvlVphenol, A solution of 4-{2-bromo-ethyi)-phehoi (EXAMPLE 5; 4.5 g, 22.4 mmol), piperidine (3.3 mL, 33.5 mmol), and N,N-diisopropylethylamine (5.8 mL, 33.5 mmol) in CH3CN (100 mL) was stirred at 60 °C for 18 h. The resulting solution was cooled to room temperature and concentrated under reduced pressure to yield a pale orange solid. Diethyl ether (100 mL) was added, and the title compound was collected by filtration as an off-white solid (4.6 g, 100% crude yield), TLC (Si02, 5% 2 M NHain CH3OH/CH2CI2): Rf = 0.19. MS (ESI): mass calculated for C13H19NO2, 20 205.15; m/z found, 206.1 M+H]+. 1H NMR {400 MHz, CD3OD): 7.07-7.04 (m 2H), 6.74-6.71 (m, 2H), 3.32-3.30 (m, 2H), 3,14-3.11 (m, 3H), 2.87-2.80 (m, 1H), 1.82-1.67 (m, 6H), 1.65-1.55 (m, 2H).
B. 2-l"4-(2-Piperidin-1 -vl-ethvlVphenoxvl-benzooxazole. A mixture of 4-{2-piperidin-1 -yl-ethyl)-phenoi (0.5 g, 2.43 mmol), 2-chloro-benzooxazole (304 pJL, 2.67 mmol) and Cs2C03 (1.8 g, 5.62 mmol) in acetone (10 mL) was stirred at room temperature for 48 h. The reaction mixture was filtered through diatomaceous earth, and the pad was washed with CH2CI2. The combined filtrates were concentrated under reduced pressure to an orange oil, which was purified on Si02 (40 g; 0-100% acetone/CH2CI2) to give the desired product as 30 white solid (325 mg, 42% yield). TLC (Si02, 5% 2 M NHain CH30H/CH2CI2): 93 544938 Rf = 0.36. MS (ESI): mass calculated for 020^2^02, 322.17; m/z found, 323.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.53-7.51 (m, 1H), 7.44-7.42 (m, 1H), 7.34-7.20 (m, 6H), 2.87-2.83 (m, 2H), 2.60-2.56 (m, 2H), 2.48 (brs, 2H), 1.66-1.59 (m, 6H), 1.50-1.43 (m, 2H).
EXAMPLE 30 {2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine, A. 4-[2-(Cvclohexvl-ethvl-amino1)-ethvn-phenol. To a stirring solution of 4-(2-bromo-ethyl)-phenol (EXAMPLE 5; 4.48 g, 22.3 mmol) in CH3CN (100 mL) was added cyciohexyl-ethyl-amine (5.0 mL, 33.4 mmol), followed by N,N-diisopropylethylamine (7.76 mL, 44.6 mmol). The resulting solution was stirred at 60 °C for 16 h, yielding a suspension. The suspension was allowed to cool 15 to room temperature and was filtered. The filtered solid was washed with ethyl acetate (2 x 20 mL) and dried to give a white solid (4.8 g, 87% yield). MS (ESI): mass calculated for C16H25NO, 247.19; m/z found, 248.2 [M+H]+. 1H NMR: (400 MHz, CDCI3): 7.01 (d, J= 8.6, 2H), 6.87 (d, J- 8.6, 2H), 3.32-3.17 (m, 2H), 3.15-2.98 (m, 4H), 2.30-2.21 (m, 2H), 1.77-1.59 (m, 2H), 1.57-1.46 (m, 20 5H), 1.40-1.10 (m, 3H).
B. ■f2-r4-(Benzothiazol-2-vloxv)-phenvn-ethvl)-cvciohexvl-ethvl-amine. To a stirring solution of 1-[2-(4-hydroxy-phenoxy)-ethyi]-piperidin-4-oi (495 mg, 2.0 mmol) in DMF (10 mL), was added CS2CO3 (1.3 g, 4.0 mmol) and 2-chlorobenzothiazole (0.33 mL, 2.5 mmol). The suspension was stirred at 80 °C 25 overnight. The reaction mixture was allowed to cool to room temperature and was then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified on SiOs (40 g; 0-100% acetone/CH2CI2) to give 548 mg (72% yield) of a tan solid. MS (ESI): mass calculated for C23H28N2OS, 380.19; m/z found, 381.4 [M+Hf. 1H NMR (400 30 MHz, CDCI3): 7.73 (d, J = 8.0, 1H), 7.63 (d, J = 8.0, 1H), 7.30 (t, J = 8.0, 1H), 94 544938 7.29-7.20 (m, 5H), 2.78-2.68 (m, 4H), 2.62 (dd, J = 6.8, 7.4, 2H), 2.56-2.46 (m 1H), 1.83-1.74 (m,4H), 1.66-1.57 (m, 1H), 1.21 (dd, J= 9.0, 8.6, 4H), 1.15-1.11 (m, 1H), 1.06 (t, J = 7.2, 3H).
EXAMPLE 31 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxyiic acid amide.
A suspension of 2-[4-(2-bromo-ethyl)-phenoxy]-benzothiazole (EXAMPLE 10; 10 250 mg, 0.75 mmol), nipecotamide (96 mg, 0.75 mmol) and Silicycle® dimethylamine resin (1.1 g, 1.50 mmol) in CH3CN was heated to 70 °C for 18 h. The reaction mixture was filtered, and the collected resin was washed with CH3CN. The combined filtrates were concentrated under reduced pressure to a crude solid, which was purified on Si02 (10 g; 0-100% 10% [2 M 15 NH3 in CH3OH] in ChhCh/CHsCh) to provide 135 mg (47% yield) of a white solid. MS (ESI): mass calculated for C21H23N3O2S, 381.15; m/z found, 382.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 8.10 (d, J = 8.1, 1H), 7.75 (dd, J = 8.0, 0.8, 1H), 7.42 (dt, J = 7.4, 1.3, 1H), 7.21 (br s, 1H) 6.42 (br s, 1H), 3.05 (br d, J = 10.3, 1H), 2.95-2.80 (m, 3H), 2.80-2.62 (m, 2H), 2.47-2.40 (m, 1H), 2.36 (d, J 20 =11.5, 1H), 2.08 (t, J= 10.5, 1H), 1.98 (d, J=11,0, 1H), 1.76-1.63 (m, 1H), 1.63-1.50 (m, 2H).
EXAMPLE 32 1 -(1 -{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethy!}-piperidin-4-yl)-3-methyi-1,3-dihydro-benzoimidazol-2-one.
O' 95 544938 A. Toluene-4-sulfonic acid 244-fbenzothiazol-2~vloxv)-phenvn-ethy{ ester. To a stirring solution of 2-[4-(benzothiazol-2-yloxy)-phenyl]-ethanol (EXAMPLE 10; 12.25 g, 45.2 mmol) in CH2CI2 (225 mL) was added p-toluenesulfonyl chloride (17.23 g, 90 mmol) and TEA (31 mL, 225 mmol). The mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (400 mL). The solution was washed with sat. aq. NaHCOs (3 x 200 mL), dried (Na2S04), and concentrated under reduced pressure. The resultant oil was dissolved in 10 CH2CI2 and purified on Si02 (300 g; CH2CI2) to give a tan solid (8.8 g, 45% yield). MS (ESI): mass calculated for C^HigN^Sa, 425.08; m/z found, 426.0 [M+H]+. 1H NMR (400 MHz, CDCI3); 7.70 (q, J= 9.7, 4H), 7.39 (t, J= 7.8, 1H), 7.32-7.17 (in, 8H), 4.23 (t, J = 6.9, 2H), 2.99 (d, J = 6.9, 2H), 2.43 (s, 3H).
B. 1-n-(2-f4-(Benzothiazol-2-vloxv)-phenvi1-ethvlVpiperidin-4-vn-3-methvl-1.3-15 dihvdro-benzoimidazol-2-one. To a stirring solution of toiuene-4-suifonic acid 2-[4-(benzothiazo!-2-yloxy)-phenyl]-ethyl ester (400 mg, 0.94 mmol) in CH3CN (5 mL), was added 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (653 mg, 2.82 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure and purified on Si02 20 (12 g; 50% acetone/CH2CI2) to give a clear oil (16 mg, 3.3% yield). MS (ESI): mass calculated for C^H^N^S, 484.19; m/z found, 485.5 [M+H]+, 1H^NMR (400 MHz, CD3OD): 7.75 (d, J = 7.9, 1H), 7.65 (d, J = 8.1, 1H), 7.41-7.29 (m, 7H), 7.13 (m, 3H), 4.37 (m, 1H), 3.40 (s, 3H), 3.25 (d, J= 11.8, 2H), 2.94 (m, 2H), 2.75 (m, 2h), 2.57 (qd, J= 12.6, 3.7, 2H), 2.33 (t, J= 11.3, 2H), 1.81 (d, J 25 =12.2, 2H), EXAMPLE 33 0 96 544938 1 -{2-[4-(Benzothiazol-2-yIoxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester.
A. 1-r2-(4-Hvdroxv-phenvlVethvn-Diperidine-4-carboxviic acid methyl ester. To 5 a stirring solution of 4-(2-bromo-ethyl)-phenol (EXAMPLE 5; 5.05 g, 25 mmol) in CH3CN (100 mL) was added piperidine-4-carboxylic acid methyl ester (5.07 mL, 37.5 mmol), followed by A/,/V-diisopropylethyIamine (8.7 mL, 50 mmol). The reaction mixture was stirred at 60 °C for 16 h, and then allowed to cool to room temperature. CH2CI2 (250 mL) was added, and the resulting solution was 10 washed with H20 (2 x 30 mL), dried, filtered, and then concentrated under reduced pressure to afford 5.2 g (79%) of a tan solid. MS (ESI): mass calculated for C15H2iN03, 263.15; m/z found, 264.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 6.97 (d, J = 8.2, 2H), 6.70 (d, J = 8.6, 2H), 3.67 (s, 3H), 2.99 (d, J= 11.5, 2H), 2.76-2.68 (m, 2H), 2.60-2.54 (m, 2H), 2.40-2.30 (m, 1H), 2.18 (t, 15 J = 10.8, 2H), 1.99-1.90 (mf 2H), 1.90-1.78 (m, 2H).
B. 1 -(2-r4-(Benzothiazol-2-vloxv)-phenvn-ethvl)-piperidine-4-carboxvlic acid methyl ester. To a stirring solution of 1-[2-(4-hydroxy-phenyl)-ethyl]-piperidine-4-carboxylic acid methyl ester (790 mg, 3.0 mmol) in DMF (15 mL), was added CS2CO3 (1.95 g, 6.0 mmol) and 2-chlorobenzothiazole (0.47 mL, 3.9 mmol).
The suspension was heated to 100 °C and stirred overnight. The reaction mixture was allowed to cool to room temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified on SiC>2 (40 g; 0-100% acetone/CH2CI2) to give 1.04 g (87% yield) of a tan solid. MS (ESI): mass calculated for C22H24N2O3S, 25 396.15; m/z found, 397.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 7.8, 1H), 7.65 (d, J = 7.8, 1H), 7.38 (t, J = 7.6, 1H), 7.28-7.25 (m, 5H), 3.69 (s, 3H), 3.00-2.93 (m, 2H), 2.83 (dd, J = 7.6, 3.0, 2H), 2.61 (dd, J = 7.6, 3.0, 2H), 2.38-2.28 (m 1H), 2.11 (t, J= 10.4, 2H), 1.98-1.89 (m, 2H), 1.87-1.74 (m, 2H). 97 544938 PCT/US2O04/0243O9 EXAMPLE 34 OyU 0 (1-{2-[4-(Benzothiazo[-2-yloxy)-pheny!]-ethyl}-p!peridin-4-y[)-(4-methyl-piperazin-1 -yl)-methanone.
A. 1 -f2-f4-(Benzothiazol-2-vloxv)-phenvn-ethvll-piperidine-4-carboxvlic acid trifluoroacetic acid salt. To a solution of 1-{2-[4-(benzothiazoI-2-y!oxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester (EXAMPLE 33; 4.6 g, 11.7 mmol) in 3:1 THF/CH3OH (100 mL), was added lithium hydroxide (1.1 g, 46.6 10 mmol) in H2O (25 mL). This dark yellow solution was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in CH3OH and purified by reversed-phase HPLC to give the title compound as a light yellow solid (3.9 g, 68% yield), MS (ESi): mass calculated for C21H22N2O3S, 382.14; m/z found, 383.4 [M+H]+, 15 B. (1-f244-(Benzothiazol-2-vloxv)-phenvn-ethvQ-piperidin-4-viH4-methvl-piperazin-1 -vO-methanone. To a mixture of 1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid TFA salt (300 mg, 0.6 mmol) in CH2Ci2 (15 mL) and a drop of DMF, was added oxalyl chloride (0.11 mly, 1.2 mmol). The mixture was stirred at room temperature for 1 h. The resulting 20 mixture was concentrated under reduced pressure. The residue was dissolved in CH2CI2 (15 mL), and A/-methylpiperizine (0.2 mL, 1.8 mmol) was added.
This reaction mixture was stirred at room temperature for 1 h, diluted with CH2CI2 (100 mL), washed with H20, sat. aq. NaHC03 then brine, dried (Na2SC>4), and filtered. The filtrate was concentrated under reduced pressure, 25 and the residue was purified on SiC>2 (40 g; 0--1Q% 2 M NH3 in CH3OH/CH2CI2) to give the title compound (240 mg, 86%). MS (ESI): mass calculated for C26H32N203S, 464.22; m/z found, 465.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.72 (d, J = 7.6, 1H), 7.65 (d, J = 7.6, 1H), 7.37 (t, J = 7.6, 1H), 7.29-7.22 (m, 5H), 3.64 (br s, 2H), 3.51 (br s, 2H), 3.06 EXAMPLE 35 {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cyclohexyI-ethyl-amine.
A. r3-(4-BenzvlQxv-phenvh-propvl1-cvclohexvl-ethvl-amine. To a solution of 3-(4-benzyloxy-phenyl)-propyl-1-bromide (504 mg, 1.65 mmol) and /V-ethylcyclohexylamine (497 jiL, 3.30 mmol) in CH3CN (15 mL) was added k2co3 (510 mg, 3.69 mmol). The reaction mixture was heated at reflux for 20 h. The mixture was filtered and then concentrated under reduced pressure to a golden oil, which was purified on Si02 (10 g; 50% acetone/ChfeCfe) to give 484 mg (83% yield) of the desired product as a clear and colorless oil. TLC 15 (SiC>2, acetone): Rf = 0.13. MS (ESI): mass calculated for C24H33NO, 351.26; m/z found, 352.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.50-7.28 (m, 5H), 7.12 (d, J = 8.6, 2H), 6.90 (d, J = 8.6, 2H), 5.06 (s, 2H), 2.60-2.45 (m, 7H), 1.78 (br s, 6H), 1.20 (br s, 4H), 1.05 (t, J = 7.1, 4H). ^ B. 4-f3-(Cvclohexvl-ethvl-aminoVpropvl1-phenol. To a solution of [3-(4- benzyloxy-phenyl)-propyl]-cyclohexyl-ethyI-amine (420 mg, 1.19 mmol) in 1:1 ethanol/ethyl acetate (16 mL) was added Pd on carbon (10 wt %, 46 mg). The mixture was placed on a Parr hydrogenator at 40 psi of H2 for 20 h. The resultant mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 308 mg (99% yield) of the 25 desired product as a golden oil. TLC (Si02, acetone): Rf = 0.18. MS (ESI): mass calculated for C17H27NO, 261.21; m/z found, 262.3 [M+Hf. 1H NMR (400 MHz, cdci3): 7.00 (d, J = 8.5, 2H), 6.75 (d, J = 8.5, 2H), 2.65 (br s, 5H), 2.54 (t, J = 7.6, 2H), 1.82 (br s, 6H), 1.30-1.05 (m, 8H).
C. (3-r4-(Benzooxazol-2-vloxv)-nhenvn-propvl)-cvclohexvl-ethvl-amine, To a 30 mixture of 4-[3-(cyclohexyl-ethyl-amino)-propyl]-phenol (283 mg, 1.08 mmol) 99 544938 and Cs2C03 {885 mg, 2.72 mmol) in acetone (15 mL) at 5 °C was added 2-chloro-benzooxazole (155 (iL, 1.36 mmol). The reaction mixture was aiiowed to warm slowly to room temperature overnight, then was filtered. The filtrate was concentrated under reduced pressure to give a golden oil, which was 5 purified on Si02 (10 g; acetone) to give 333 mg (81% yield) of the desired product as a golden oil. TLC (Si02, acetone): Rf = 0.12. MS (ESI): mass calculated for C24H3oN202] 378.23; m/z found, 379.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.61 (d, J = 7.3, 1H), 7.49 (d, J = 7.8, 1H), 7.39 (d, J = 8,6, 2H), 7.38-7.25 (m, 4H), 2.62 (t, J = 7.5, 2H), 2.65-2.35 (m, 8H), 1.67 (br s, 5H), 10 1.19-1.10 (m, 4H), 0.95 {t,J= 7.1, 3H).
EXAMPLE 36 1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyI}-piperidin-4-ol.
A. 1 -[3-(4-Hvdroxv-phenvlVpropyl1-piperidin-4-ol. A solution of 4-(3-bromo-propyl)-phenol (EXAMPLE 6; 1.42 g, 6.6 mmol), 4-hydroxypiperidine hydrochloride (908 mg, 6.6 mmol), and A/,A/-diisopropylethyamine (2,2 mL, 12.3 mmol) in CH3CN {20 mL) was stirred at 60 °C for 18 h. The reaction mixture 20 was cooled to room temperature, and the solvent was removed under reduced pressure to yield an off-white solid. This material was dissolved in CH2CI2 (200 mL), and the solution was washed with H20 (2 x 50 mL), dried (Na2S04), filtered and concentrated under reduce pressure to yield a white solid. Diethyl ether was added, and the title compound was collected by filtration (1.4 g, 90% 25 yield). TLC (Si02, 5% 2 M NH3in CH3OH/CH2CI2): Rf = 0.05. MS (ESI): mass calculated for C14H2iN02, 235.16; m/z found, 236.2 [M+Hf. 1H NMR (400 MHz, CD3OD): 6.96-6.94 (m, 2H), 6.64-6.61 (m, 2H), 3.89-3.82 (m, 1H), 3.29-3.20 (m, 4H), 3.02-2.95 (m, 4H), 2.52 (t, J = 7.4, 2H), 1.95-1.87 (m, 4H), 1.68-1.60 (m, 2H).
B. 1-(3-r4-(Benzooxazol-2-vloxvVphenvn-propvl)-piperidin-4-oi. A mixture of 1-[3-(4-hydroxy-phenyi)-propyl]-piperidin-4-ol (0.4 g, 1.69 mmol), 2-chloro- 100 544938 benzooxazoie (176 jiL, 1.54 rnmol) and Cs2C03 (1.45 g, 4.45 mmol) in acetone (8.0 mL) was stirred at room temperature for 48 h. The resulting mixture was filtered through diatomaceous earth, which was then washed with CH2CI2. The combined filtrates were concentrated under reduced pressure to a yellow oil, 5 The oil was purified on Si02 (40 g; 0-100% acetone/CH2CI2) to give a white solid, which was dissolved in CH2CI2. The solution was washed with 1 M NaOH (3x5 mL) then H20 (5 mL), dried (Na2S04), filtered, and concentrated under reduced pressure to yield the title compound as a white solid (98 mg, 16.4% yield). TLC (Si02t 5% 2 M NH3in CH3OH/CH2CI2): Rf = 0.14. MS 10 (ESI): mass calculated for C2iH24N203, 352.18; m/z found, 363.1 [M+H]+. 1H NMR (400 MHz, CDCi3): 7.66-7.51 (m, 1H), 7.44-7.42 (m, 1H), 7.34-7.21 (m, 6H), 3.72-3.69 (m, 1H), 2.79-2.76 (m, 2H), 2.67 (t, J = 7.8, 2H), 2.38 (t, J= 7,6, 2H), 2.15-2.11 (m, 2H), 1.98-1.80 (m, 3H). 1.65-1.55 (m, 3H), 1.42 (m, 1H).
EXAMPLE 37 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-phenyi-piperidin-4-ol.
A. 1 -r2-(4-Hvdroxv-phenoxv)-ethvll-4-phenvj-piperidin-4-ol. To a solution of 4-20 (2-bromo-ethoxy)-phenoi (EXAMPLE 3; 8.0 g, 36.8 mmol) and 4-hydroxy-4-phenylpiperidine (8.2 g, 46.3 mmol) in CH3CN (150 mL) was added DIEA (7.0 mL, 40.2 mmol). The mixture was stirred for 20 h at room temperature and for an additional 4 h at 65 °C, then was concentrated under reduced pressure to give a brown solid. The solid was dissolved in ethyl acetate (250 25 mL), and the solution was washed with H20 (250 mL, 100 mL), dried (MgS04), and concentrated under reduced pressure to give a brown solid. The solid was purified on Si02 (120 g; 0-100% acetone/CH2CI2) e to give 8.9 g (77% yield) of the desired product as a tan solid. TLC (Si02, acetone): Rf = 0.42. MS (ESI): mass calculated for Ci9H23N03, 313.17; m/z found 314.2 [M+H]+. 1H NMR 30 (400 MHz, CDCIs): 7.52 (d, J = 8.6, 2H), 7.37 (t, J = 7.3, 2H), 7.27 (m, 1H), 101 544938 6.75 (s, 4H), 4.08 (t, J = 5.8, 2H), 3.05-2.90 (m, 2H), 2.88 (t, J = 5.8, 2H), 2.80-2.62 (m, 2H), 2.31-2.18 (m, 2H)r 1.81 (d, J= 11.8, 2H).
B. 4-Phenvl-1-(2-l4-f1-f2-trimethvlsilanvl-ethoxvmethvl)-1H-benzoimidazol-2-vloxv1-phenoxv)-ethv0-piperidin-4-ol. To a mixture of 2-chloro-1-(2- trimethylsilanyl-ethoxymethyi)-1 H-benzoimidazole (EXAMPLE 7; 630 mg, 2.2 mmol) and 1-[2-(4-hydroxy~phenoxy)-ethyl]-4-phenyI-piperidin-4-ol (690 mg, 2.2 mmol) in DMF (10 mL) was added Cs2C03 (1.5 g, 4.6 mmol). The reaction mixture was stirred at 100 °C for 18 h, and then partitioned in 1:1 ethyl acetate/H20 (50 mL). The organic layer was collected, dried (MgS04), and 10 concentrated under reduced pressure to give a clear brown oil, which was purified on Si02 (35 g; acetone) to give 867 mg (70% yield) of the desired product as a clear golden oil. TLC (Si02, acetone): Rf = 0.38. MS (ESI): mass calculated for C32H4iN304Si, 559.29; m/z found, 560.3 [M+H]+, 1H NMR (400 MHz, CDCI3): 7.55 (m, 3H), 7.38 (m, 3H), 7.30-7.20 (m, 5H), 6.99 (d, J = 15 9.0, 2H), 5.55 (s, 2H), 4.17 (t, J = 5.9, 2H), 6.37 (m, 2H), 2.92 (m, 5H), 2.65 (t, j = 12.4, 2H), 2.21 (t, J = 15.9, 2H), 1.81 (d, J = 12.1, 2H), 0.96 (t, J = 8.1, 2H).
C. 1 A2-\A-( 1 H-Benzoimidazol-2-vloxv)-phenoxv]-ethvlM-phenvl-piperidin-4-ol. To a solution of 4-phenyl-1-(2-{4-[1-(2-trimethylsilanyl-ethoxymethyI)-1H-benzoimidazof-2-yloxy]-phenoxy}-ethyl)-piperidin-4-ol (816 mg, 1.46 mmol) in THF (5 mL) containing A/,/V,/V,A/-tetramethylethylenediamine (TMEDA, 2.2 mL, 14.6 mmol), was added a 1 M THF solution of tetrabutylammonium fluoride (TBAF, 15 mL, 15 mmol). The mixture was stirred at 55 °C for 5 h, then was concentrated under reduced pressure. The resulting oil was dissolved in diethyl ether(100 mL), and the solution was washed with H20 (3 x 75 mL), 25 dried (MgS04), filtered, and concentrated under reduced pressure to give a white solid. Diethyl ether was added, and filtration gave the desired product as a white solid (155 mg, 25% yield). TLC (Si02f acetone): Rf = 0.16. MS (ESI): mass calculated for C26H27N303, 429.21; m/z found, 430.2 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 12.23 (brs, 1H), 7.48 (d, J= 7.3, 2H), 7.35-7.25 (m, 30 6H), 7.20 (t, J = 7.4, 1H), 7.10-7.04 (m, 2H), 7.00 (d, J = 9.0, 2H), 4.80 (s, 1H), 4.13 (t, J = 5.8, 2H), 2.76 (t, J = 5.8, 2H), 2.58-2.48 (m, 2H), 1.94 (dt, J = 12.7, 4.0, 2H), 1.58 (d, J= 12.1, 2H). 102 544938 EXAMPLE 38 H {2-[4-(1H-Benzoimidazol-2-yloxy)-phenyI]-ethyl}-cyclopropyimethyl-propyl-amine.
A. 4-f2-(Cvclopropvlmethvl-propvl-aminoVethvH-phenol. To a solution of 4-(2-bromo-ethyl)-phenol (EXAMPLE 5; 5.0 g, 25,0 mmol) in CH3CN (100 mL) was added cyclopropylmethyl-propyl-amine (5.4 mL, 37,5 mmol), followed by N,N-diisopropylethylamine (8.70 mL, 50.0 mmol). The resulting solution was stirred at 60 °C for 16 h, yielding a suspension, which was cooled to room temperature and filtered. The filtered solid was washed with ethyi acetate (2 x 20 mL) and dried to give a white solid (5,7 g, 98% yield), MS (ESI): mass calculated for C15H23NO, 233.18; m/z found, 234.1 [M+H]+. 1H NMR (400 MHz, DMSO-c/e): 7.01 (d, J = 8.6, 2H), 6.87 (d, J = 8.6, 2H), 3.34-3,30 (m, 2H), 3.19- 3.04 (m, 2H), 2.94-2.75 (m, 4H), 1.75-1.56 (m, 2H), 1.16-0.99 (m, 1H), 0.95-0.87 (m, 3H), 0.68-0.53 (m, 2H), 0.44-0,32 (m, 2H).
B. (2-r4-(1H-Benzoimidazol-2-vloxv)-phenvn-ethvD-cvclopropvlmethyl-propvl-amine. A mixture of 2-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H- / benzoimidazole (EXAMPLE 7; 707 mg, 2.5 mmol), 4-[2-(cyciopropyimethyl- propyl-amino)-ethyl]-phenol (467 mg, 2.0 mmol), and Cs2C03 (1.3 g, 4,0 mmol) in DMF (10 mL) was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature, and then partitioned in 1:1 ethyl acetate/H20 (200 mL). The organic layer was collected, dried (MgSCU), and concentrated under reduced pressure to give a clear brown oil, which was purified on Si02 (40 g; 0-100% acetone/CH2CI2), giving 729 mg (76% yield) of a clear golden oil. MS (ESI): mass calculated for C28H4iN302Si, 479.30; m/z found, 480.5 |M+H]+. 1H NMR (400.MHz, CDCI3): 7.63-7.58 (m, 1H), 7.49-7.39 (m, 1H), 7,31 (s, 4H), 7.26-7.22 (m, 2H), 5.58 (s, 2H), 3.69 (t, J= 8,2, 2H), 2.89-2.79 (m. 4H), 22.63-2.58 (m, 2H), 2.48 (d, J = 6.5, 2H), 1.61-1.50 (m, 2H), 1.01-0.91 (m, 6H), 0.59- 0.53 (m, 2H), 0,20-0.15 (m, 2H), 0.1 (s, 9H). 103 544938 C. (2-l4-( 1 H-Benzoimidazol-2-vloxvVphenvll-ethviVcvclopropvlmethvl-propvi-amine. To a solution of cyclopropylmethyl-propyl-(2-{4-[1-(2-trimethyIsilanyI-ethoxymethyl)-1H-benzoimidazoi-2-yloxy]-phenyl}-ethyl)-amine (411 mg, 0.87 mmol) in THF (5 mL), TBAF (1 M in THF, 2.57 mL, 2.57 mmol) was added via 5 syringe, and the mixture was stirred at reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was purified on Si02 (40 g; 0-20% CH30H/CH2Ci2)s giving 284 mg (95% yield) of a clear oil. MS (ESI); mass calculated for C22H27N3O, 349.22; m/z found, 350.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.34 (brs, 2H), 10 7.18-7.05 (m, 6H), 2.82-2.70 (m, 4H), 2.69-2.62 (m, 2H), 2.52 (d, J = 6.8, 2H), 1.61-1.50 (m, 2H), 0.91 (t, J = 6.8, 4H), 0.57-0.51 (m, 2H), 0.16 (dd, J= 5.3, 5.1, 2H).
EXAMPLE 39 Cyclohexy!-ethyl-{2-[4-( 1 -methyl-1 H-benzoimidazol-2-yloxy)-pheny]]-ethyi}- A mixture of 4-[2-(cyclohexyl-ethyl-amino)-ethyi]-phenol (247 mg, 1.0 mmol), N-20 methyl benzimidazole (EXAMPLE 8; 200 mg, 1.2 mmol), and Cs2C03 (652 mg, 2.0 mmol) in DMF (3 mL) was stirred at 100 °C for 16 h. The reaction mixture was cooled and filtered through diatomaceous earth, which was then washed with ethyl acetate (30 mL). The combined filtrates were washed with H20 (3 x 10 mL) then brine (10 mL), dried (Na2S04), filtered, and concentrated under 25 reduced pressure. The crude material was purified on Si02 (10 g; 0-100% 10% [2 M NH3 in CH3OH] in CH2Cl2/CH2CI2) to provide 105 mg (28% yield) of a brown oil. MS (ESI): mass calculated for C24H3iN30, 377.53; m/z found, 378.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.52 (d, J =7.2, 1H), 7.63-7.58 (m, 1H), 7.33-7.18 (m, 7H), 3.75 (s, 3H), 2.81-2.70, m, 4H), 2.68 (q, J = 7.1, 2H), 2.60- amine. 104 544938 2.50 (m, 1H), 1.90- 1.80 (m, 4H), 1.67 (d, J= 12.3, 1H), 1.35-1.18 (m, 4H), 1.15-1.05 (m, 1H), 1.12 (t, J= 7.1, 3H).
EXAMPLE 40 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-2-hydroxy-propyi}-4-phenyl-piperidin-4-ol.
A. 2-(4-Benzvloxy-phenoxvmethvO-oxirane. To a solution of 4-(benzyloxy)phenol (15.0 g, 74.9 mmol) and epichlorohydrin (30 mL, 384 mmol) in DMF (200 mL) was added Cs2C03 (51.2 g, 157 mmol). The mixture was heated to 75 °C for 3 days. The reaction mixture was cooled to room temperature, and then partitioned in 1:1 ethyl acetate/H20 (600 mL). The \ organic layer was collected, washed with H20 (3 x 250 mL), dried (MgSC>4), filtered, and concentrated under reduced pressure to give 38 g of a clear, dark brown liquid. The liquid was purified on Si02 (300 g; 50-100% CH2CI2/hexanes) to give the desired product as a white solid (13 g, 68% yield). TLC (Si02, CH2Cl2): Rf = 0.64. 1H NMR (400 MHz, CDCI3): 7.55-7.28 {jm, 5H), 6.91 (d, J= 9.3, 2H), 6.86 (d, J- 9.3, 2H), 5.03 (s, 2H), 4.17 (dd, J = 11.0, 3.2, 1H), 3.95-3.88 (m, 1H), 3.36-3.33 (m, 1H), 2.91 (t, J = 4.8, 1H), 2.75 (dd, J = 4.9, 2.6, 1H).
B. 1-r3-(4-Benzvloxv-phenoxvV2-hvdroxv-propvn-4-phenvl-piperidin-4-ol. To a solution of 2-(4-benzyloxy-phenoxymethyl)-oxirane (1.50 g, 5.85 mmol) and 4-hydroxy-4-phenylpiperidine (1.30 g, 7.33 mmol) in ch3cn (50 mL) was added K2CC>3 (1.0 g, 7.23 mmol). The mixture was heated at reflux for 20 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a white solid, which was purified on Si02 (40 g; acetone) to give 1.4 g (56% yield) of the desired product as a white solid. TLC (Si02, acetone): Rf = 0.36. MS (ESI): mass calculated for c27h31no4, 433.23; m/z found, 434.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.56-7.23 (m, 10 H), 105 544938 6.93 (d, J = 9.2, 2H), 6.88 (d, J = 9.2, 2H), 5.03 (s, 2H), 4.77 (s, 2H), 3.93 (br d, J= 10.8, 2H), 3.81 (t, J= 7.2, 1H), 2.80-2.60 (m, 2H), 2.50-2.35 (m, 4H), 1.97-1.90 (m, 2H), 1.60-1.50 (d, J = 13.4, 2H), C. 1-f2-Hvdroxv-3-(4-hvdroxv-phenoxv'>-propvll-4-phenvi-piperidin-4-ol. To a 5 solution of 1-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-4-phenyl-piperidin-4- ol (1.3 g, 3.0 mmol) in 1:1 ethanol/ethyl acetate (50 mL) was added Pd on carbon (10 wt %, 165 mg). The mixture was placed on a Parr hydrogenator at 40 psi of H2 for 20 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 1.0 g 10 (100% yield) of desired product as a white solid. TLC (Si02, acetone): Rf = 0.27. MS (ESI): mass calculated for C2oH25N04! 343.18; m/z found, 344.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.61 (d, J = 8.1, 2H), 7.42 (t, J = 7.4, 2H), 7.30 (t, J = 7.3, 1H), 6.90 (d, J - 9.0, 2H), 6.81 (d, J = 9.0, 2H), 4.25 (br s, 1H), 4.05-3.95 (m, 2H), 3.10-2.92 (m, 2H), 2.80-2.60 (m, 4H), 2.30-2.20 (m, 15 2H), 1.81 (d,J= 11.8, 2H).
D. 143-r4-(Benzooxazol-2-vloxv'l-phenoxv1-2-hvdroxv-propvl>-4-phenvl-pjperidin-4-ol. To a mixture of 1-[2-hydroxy-3-(4-hydroxy-phenoxy)-propyl]-4-phenyl-piperidin-4-ol (251 mg, 0.73 mmol) and Cs2C03 (667 mg, 2.05 mmol) in acetone (10 mL) at 5 °C, was added 2-ch!oro-benzooxazole (108 (iL, 0.95 mmol). The reaction mixture, left on ice, warmed to room temperature overnight and was then filtered. The filtrate was concentrated under reduced pressure to give a golden oil, which was purified on Si02 (10 g; acetone) to give 127 mg (38% yield) of the desired product as a white solid. TLC {Si02, acetone): Rf = 0.27. MS (ESI): mass calculated for C27H28N205, 460.20; m/z 25 found, 461.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.60 (d, J = 6.6, 1H), 7.55-7.35 (m, 5H), 7.32-7.25 (m, 4H), 7.20 (t, J = 7.3, 1H), 7.06 (d, J = 9.1, 2H), 4.78 (s, 1H), 4.10-3.85 (m, 3H), 2.80-2.65 (m, 2H), 2.55-2.35 (m, 4H), 1.95 (t, J = 13.1, 2H), 1.59 (d, J= 13.2, 2H). 106 544938 EXAMPLE 41 1-[2-(4-Benzooxazol-2-yfmethyi~phenoxy)-ethyi]-piperidine-4-carboxylic acid ethyl ester.
A. 4-Benzooxazol-2-vlmethvl-pheno). A mixture of 4-hydroxyphenyiacetic acid (35 g, 230 mmol) and 2-aminophenol (43 g, 400 mmol) was heated at 180°C for 3 h and then cooled to room temperature. The resultant solid was ground and dissolved in THF (200 mL), and carbonyldiimidazole (27 g, 170 mmol) was added. The solution was stirred at 60 °C overnight. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (400 mL) and H2O (300 mL). The organic layer was concentrated under reduced pressure. The resultant oil was dissolved in CH2CI2 and purified on Si02(200 g; 0-50% acetone/CH2Cl2) to give a brown solid (31 g, 40% yield). 15 MS (ESI): mass calculated for Ci4H-nN02, 225.08; m/z found, 226.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.62 (m, 1H), 7.53 (m, 1H), 7.32 (m, 2H), 7.17 (d, J = 8.5, 2H), 6.75 (d, J = 8.5, 2H), 4.18 (s, 2H).
B. 2-f4-(2-Bromo-ethoxv)-benzvn-benzooxazole, To a stirring solution of 4-benzooxazol-2-ylmethyl-phenol (5 g, 22.2 mmol) in CH3CN (100 mL) wa4 added Na2C03 (6.4 g, 46.6 mmol) and dibromoethane (7.9 mL, 88.8 mmol). The resulting suspension was heated to 70°C for 72 h and filtered while hot. The filtrate was concentrated under reduced pressure. The resulting solid was suspended in diethyl ether and filtered, and the filtrate was concentrated under reduced pressure. The resultant oil was dissolved in CH2CI2 and purified on 25 SiC>2 (110 g; CH2CI2) to give an off-white solid (1g, 13.7% yield). MS (ESI): mass calculated for Ci6Hi4BrN02, 331.02; m/z found, 332.0 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.62 (m, 1H), 7.53 (m, 1H), 7.34 (m, 2H), 7.29 (d, J= 8.6, 2H), 6.92 (d, J = 8.7, 2H), 4.28 (t, J = 5.9, 2H), 4.23 (s, 2H), 3.67 (t, J- 5.9, 2H). 107 544338 C. 1 -f2-f4-Benzooxazol-2-vlmethvl-phenoxv)-ethvn-piperidine-4-carboxviic acid ethvl ester. To a stirring solution of 2-[4-(2-bromo-ethoxy)-benzyl]-benzooxazole (0.5 g, 1.5 mmol) in CH3CN (7.5 mL) was added ethyl isonepicotate (0.7 mL, 4.5 mmol). The mixture was stirred at room 5 temperature for 48 h, then concentrated under reduced pressure. The resultant oil was dissolved in CH2CI2 and purified on Si02 (40 g; 0-25% acetone/CHaCfe) to give an off-white solid (275 mg, 45% yield). MS (ESI): mass calculated for C24H28N2O4, 408.20; m/z found, 409.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.67 (m, 1H), 7.45 (m, 1H), 7.28 (d, J = 9.0, 4H), 6.88 (d, J 10 = 8.7, 2H), 4.20 (s, 2H), 4.12 (q, J = 7.1, 2H), 4.08 (t, J = 5.9, 2H), 2.95 (d, J = 11.5, 2H), 2.77 (t, J = 5.9, 2H), 2.24 (m, 1H), 2.16 (m, 2H), 1.84 (m, 2H), 1.76 (m, 2H). 1.24 (t, J=7.2, 3H).
EXAMPLE 42 ,S- 1-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylic acid methyl ester.
A. 4-Benzothiazol-2-vlmethvl-phenol. A mixture of 4-hydroxyphenylacJtic acid 20 (15.2 g, 100 mmol) and 2-amino-benzenethiol (10.7 mL, 100 mmol) was heated at 150°C for 16 h and then cooled to room temperature. The resultant solid was ground and dissolved in CH2CI2 (400 mL). The solution was washed with 1 N HCI (2 x 50 mL) then sat. aq. NaHC03 (2 x 50 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified on Si02 (0-25 50% ethyl acetate/hexanes) to give a white solid (10.5 g, 44% yield). MS (ESI): mass calculated for Ci4HnNOS, 241.06; m/z found, 342.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.89 (dd, J = 8.6, 4.8, 2H), 7.47 (t, J = 7.8, 1H), 7.31 (t, J = 7.8, 1H), 7.18 (d, J = 8.3, 2H), 6.77 (d, J = 8.6, 2H), 4.89 (s, 1H), 4.33 (s, 2H).
B. 2-f4-f2-Bromo-ethoxvVbenzvn-benzothiazole. To a stirring solution of 4-benzothiazol-2-ylmethyl-phenol (10.5 g, 43.5 mmol) in CH3CN (100 mL) was 108 544938 added Cs2C03 (28.3 g, 87 mmol) and dibromoethane (18.7 mL, 21.8 mmoi). The resulting suspension was heated to 70 °C for 16 h, cooled to room temperature, and then dissolved in CH2CI2 (400 mL). The solution was washed with H20 (2 x 50 mL), dried, and concentrated. The resultant oil was dissolved 5 in CH2C(2 and purified on SiC>2 (0-50% ethyl acetate/hexanes) to give a white solid (7.5 g, 49.5% yield). MS (ESI): mass calculated for CieH-^BrNOS, 347.00; m/z found, 348.1 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.99 (d, J = 8.1, 1H), 7.79 (d, J = 8.1, 1H), 7.45 (t, J= 7.6, 1H), 7.36-7.25 (m, 3H), 6.89 (d, J = 8.8, 2H), 4.38 (s, 2H), 4.28 (t, J = 6.3, 2H), 3,63 (t, J = 6.3, 2H). 10 C. 1-r2-(4-Benzothiazol-2-vlmethvl-phenoxv)-ethvn-piperidine-4-carboxvlic acid methvl ester. To a stirring solution of 2-[4-(2-bromo-ethoxy)-benzyi]-benzothiazole (1.0 g, 2.9 mmol) in CH3CN (20 mL) was added methyl isonepicotate (0.7 mL, 55.7 mmo!) and /\/,A/-diisopropylethylamine (1.5 mL, 8.6 mmoi). The mixture was heated to 60 °C for 16 h, cooled to room temperature, 15 and then dissolved in CH2CI2 (100 mL), The solution was washed with H20 (2 x 20 mL), dried, and concentrated. The resultant oil was dissolved in CH2CI2 and purified on Si02 (0-15% CH3OH/CH2CI2) to give a white solid (1.1 g, 92% yield). MS (ESI): mass calculated for C23H26N203S, 410.17; m/z found, 411.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.98 (d, J= 8.3, 1H), 7.76 (d, J= 8.3, 20 1H), 7.42 (t, J = 7.8, 1H), 7.33-7.24 (m, 3H), 6.88 (d, J = 8.8, 2H), 4.36 (s, 2H), 4.07 (t, J = 6.1, 2H), 3.66 (s, 3H), 2.97-2.90 (m, 2H), 2.76 (t, J = 6.1, 2H)f, 2.33-2.24 (m 1H), 2.15 (t, J = 11.4, 2H), 1.93-1.86 (m, 2H), 1.83-1.72 (m, 2H).
Example 43 3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-cyclopropyl-amino)-propionic acid trifluoroacetic acid salt.
A. 342-(4-Hvdroxv-phenoxvVethvlaminol-propionic acid ethvl ester. To a 30 stirring solution of 4-(2-bromo-ethoxy)-phenoI (EXAMPLE 3; 2.4 g, 11 mmoi) in O 109 544938 CH3CN (50 mL) was added 3-amino-propionic acid ethy! ester hydrochioride (3.4 g, 22 mmol) followed by A/,A/-diisopropylethylamine (7.7 mL, 44 mmol). The mixture was stirred at 60 °C for 16 h, allowed to cool to room temperature, and then dissolved in CH2CI2 (100 mL). The resulting solution was washed 5 with H20 (2x15 mL), dried, filtered, and then concentrated under reduced pressure to afford a brown oil, which was used in the next step, B. 3-(2-r4-(Benzothiazol-2-vloxv)-phenoxv1-ethvlamino)-propionic acid ethyl ester. To a stirring solution of 3-[2-(4-hydroxy-phenoxy)-ethylamino]-propionic acid ethyl ester (11 mmol) in DMF (30 mL), was added CS2CO3 (10.8 g, 33 10 mmol) and 2-chlorobenzothiazole (2.72 mL, 22 mmol). The suspension was stirred at 100 °C overnight. The reaction mixture was allowed to cool to room temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and purified on S1O2 (100 g; 0-100% CH3OH/CH2CI2), giving 1.9 g (45% yield) of a light brown oil, MS (ESI): mass 15 calculated for C22H22N2O4S, 386.13; m/z found, 387.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.66 (d, J = 8.1, 1H), 7.58 (d, J = 8.3, 1H), 7.30 (d, J - 7.8, 1H), 7.22-7.15 (m, 3H), 6.86 (d, J = 9.1, 2H), 4.09 (dd, J = 7.1, 7.1, 2H), 4.01 (t, J = 5.3, 2H), 2.98 (t, J = 5.3, 2H), 2.92 (t, J = 6.6, 2H), 2.49 (t, J = 6,6, 2H), 2.20 (br s, 1H), 1.20 (t, J=7.1, 3H). 20 C. 3-(l2-r4-(Benzothiazol-2-vloxv)-phenoxvl-ethvl}-cvclopropvl-aminoy propionic acid ethvl ester. To a solution of 3-{2-[4-(benzothiazol-2-yloxy^)-phenoxy]-ethylamino}-propionic acid ethyl ester (500 mg, 1.29 mmol) in CH3OH (15 mL) was added acetic acid (0.73 mL, 12.9 mmoi), 3 A molecular sieves and [(1-ethoxycyciopropyl)oxy]trimethylsilane (1.55 mL, 7.7 mmoi). Sodium 25 cyanoborohydride (365 mg, 5.8 mmol) was added, and the mixture was heated at reflux overnight. The mixture was cooled, filtered and concentrated. The residue was dissolved in CH2Ci2, and the resulting solution was washed with sat. aq. NaHC03 then brine, dried, and concentrated. This residue was purified on Si02 (40 g; 10-50% ethyl acetate/hexanes), giving 374 mg (68% 30 yield) of a colorless oil. MS (ESI): mass calculated for C23H26N2O4S, 426.16; m/z found, 427.1.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.3, 1H), 7.64 (d, J = 8.1, 1H), 7.38 (d, J = 7.8, 1H), 7.29-7.22 (m, 3H), 6.94 (d, J = 9.1, 2H), 4.14 (dd, J = 7.1, 7.1, 2H), 4.10 (t, J = 6.1, 2H), 3.07 (t, J = 7.1, 2H), 3.05 110 544938 (t, J = 6.1, 2H), 2.58 (t, J = 7.3, 2H), 1.92-1.86 (m, 1H), 1.26 (t, J = 7.1, 3H), 0.54-0.43 (m, 4H).
D. 3-(f2-[4-fBenzothlazol-2-vloxv)-phenoxvl-ethvl}~cvclopropvl-aminoV propionic acid trifluoroacetic acid salt. To a solution of 3-({2-[4-(benzothiazol-2-5 yloxy)-phenoxy]-ethyl}-cyclopropyl-amino)-propionic acid ethyl ester {355 mg, 11.7 mmol) in THF (15 mL) and CH3OH (5 mL), was added lithium hydroxide (80 mg, 3.3 mmol) in H2O {10 mL). The mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure. The residue was dissolved in CH3OH and was purified by reversed-phase HPLC to 10 give the title compound (391 mg, 92% yield). MS (ESI): mass calculated for C21H22N2O4S, 398.13; m/z found, 399.1 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.73 (d, J = 8.3, 1H), 7.64 {d, J = 8.1, 1H), 7.48 (d, J = 7.8, 1H), 7.35-7.25 (m, 3H), 7.11 (d, J = 9.1, 2H), 5.17 (br s, 1H), 4.48 (t, J = 4.6, 2H), 3.81 (t, J = 4.6, 2H), 3.76 (t, J = 7.1, 2H), 3.04-2.93 {m, 3H), 1.17-1.10 (m, 2H), 1.05-0.97 (m, 2-[4-(2-Pyrrolidin-1 -yl-ethoxy)-phenoxy]-benzooxazole. j The title compound was prepared according to the procedure for EXAMPLE 11 using 1-(2-chloro-ethyl)-pyrro!idine. MS (ESI): mass calculated for Ci9H20N2O3! 324.15; m/z found, 325.1 [M+Hf. 1H NMR {400 MHz, CDCI3): 7.75 (d, J = 8.1,1H), 7.66 (d, J= 8.0, 1H), 7.40 (dt, J = 7.4, 1.3, 1H), 7.31-7.23 25 (m, 3H), 6.98 (d, J = 6.8, 2H), 4.08 (t, J - 6.3, 2H), 2.91 (t, J = 6.3, 2H), 2.67 (q, J = 7.2, 4H), 1.10 (t, J = 7.2, 6H). 2H).
EXAMPLE 44 111 544938 EXAMPLE 45 {3~[4-(Benzooxazol-2-yloxy)-phenoxy]-propyi}-dimethyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 11 using (2-chloro-propyl)-dimethyl-amine hydrochloride. MS (ESI): mass calculated for C-isHhol^Os, 312.15; m/z found, 313,1 [M+Hf, 1H NMR (400 MHz, CDCb): 7.48-7.45 (m, 1H), 7.40-7.38 (m, 1H), 7.30 (d, J= 7.9, 2H), 7.23-7.18 (m, 2H), 6.91 (d, J = 8.3, 2H), 4.09 (br sF 2H), 3.23 (br s, 2H), 2.85 (br s, 10 6H), 2.42 (brs, 2H).
EXAMPLE 46 {2-[4-(Benzooxazol-2-yioxy)-phenoxy]-ethyI}-dimethyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 11 using (2-chloro-ethyl)-dimethyi-amine hydrochloride. MS (ESI); mass j calculated for C17H18N203, 298.13; m/z found, 299.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.49-7.47 (m, 1H), 7.41-7.38 (m, 1H), 7,32-7.27 (m, 2H), 7.26-20 7.18 (m, 2H), 6.98-6.95 (m, 2H), 4.05 (t, J = 5.7, 2H), 2,72 (t, J = 5.7, 2H), 2.32 (s, 6H).
EXAMPLE 47 2-[4-(2-Azepan-1 -yl-ethoxy)-phenoxy]-benzooxazole. 112 544938 The title compound was prepared according to the procedure for EXAMPLE 11 using 1-(2-chloro-ethyl)-azepane hydrochloride, MS (ESI): mass calculated for C2iH24N203, 352.18; m/z found, 353.2 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.49-7.47 (m, 1H), 7.41-7.38 (m, 1H), 7.31-7.27 (m, 2H), 7.26-7.18 (m, 2H), 5 6.97-6.93 (m, 2H), 4.06 (t, J = 6.2, 2H), 2.94 (t, J = 6.2, 2H), 2.77-2.75 (m, 4H), 1.65-1.58 (m, 8H).
EXAMPLE 48 {2-[4-(Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine, The title compound was prepared according to the procedure for EXAMPLE 12 using (2-chloro-ethyl)-dimethy!-amine hydrochloride and 2-chlorobenzothiazole. MS (ESI): mass calculated for C17H18N2O2S, 314.11; m/z found, 315.1 [M+Hf. 15 1H NMR (400 MHz, CD3OD); 7.79-7.77 (m, 1H), 7.65-7.63 (m, 1H), 7.45-7.29 (m, 4H), 7.18-7.14 (m, 2H), .4.41 (t, J = 4.9, 2H), 3.63 (t, J = 4.9, 2H), 3.04 (s, 6H).
EXAMPLE 49 / 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzothiazoie, The title compound was prepared according to the procedure for EXAMPLE 12 using 1-(2-chloro-ethyl)-pyrrolidine and 2-chlorobenzothiazole. MS (ESI): 25 mass calculated for C-tgl-feo^C^S, 340.12; m/z found, 341.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (d, J = 7.6, 1H), 7.66 (d, J = 8.6, 1H), 7.41 (t, J = 7.4, 1H), 7.32-7.25 (m, 3H), 7.00 (d, J = 9.0, 2H), 4.16 (t, J = 6.0, 2H), 2.96 (t, J = 6.0, 2H), 2.67 (t, J = 6.6, 4H), 1.86 (quint, J = 3.5, 4H), 113 544938 EXAMPLE 50 {3-[4-(Benzothiazo[-2-yloxy)-phenoxy]~propyl}-dimethyl-amine, The title compound was prepared according to the procedure for EXAMPLE 12 using (2-chloro-propyl)-dimethyl-amine hydrochloride and 2-chlorobenzothiazole. MS (ESI): mass calculated for CieH2oN202S, 328.12; m/z found, 329.1 [M+H]+. 1H NMR (400 MHz, CDCi3): 7.72 (d, J= 8.1, 1H), 7.64 (d, J = 7.9, 1H), 7.37 (t, J = 7.5, 1H), 7.31-7.20 (m, 3H), 6.92 (d, J = 7.9, 10 2H), 4.11 (s, 2H), 3.25 (s, 2H), 2.85 (s, 6H), 2.43 (s, 2H).
EXAMPLE 51 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 12 using 1-(2-chloro-ethyl)-azepane hydrochloride and 2-chlorobenzothiazole. MS (ESI): mass calculated for C2iH24N202S, 368.16; m/z found, 369.2 [M+H]+. 1H NMR (400 MHz, CDCi3): 7.70 (d, J = 7.5, 1H), 7.65 (d, J = 7.9, 1H), 7.38-7.34 20 (m, 1H), 7.29-7.23 (m, 3H), 6.97 (br d, 2H), 4.59 (br s, 2H), 3.64 (br s, 2H), 3.46 (brs, 2H), 3.13 (brs, 3H), 2.19 (brs, 2H), 1.87 (brs, 2H), 1.72-1.58 (m, 2H).
EXAMPLE 52 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-benzothiazole, 114 544938 The title compound was prepared according to the procedure for EXAMPLE 12 using 1-(2-chloro-ethyl)-azepane hydrochloride and 2-chloro-6-methoxy-benzothiazole. MS (ESI): mass calculated for C22H26N2O3S, 398.17; m/z found, 399.2 [M+H]+. 1H NMR (400 MHz, CDC!3): 7.75 (d, J = 8.9, 1H)t 7.37-5 7.35 (m, 2H), 7.26 (br d, 2H), 7.09-7.05 (m, 3H), 4.19 (t, J = 6.1, 2H), 3.95 (s, 3H), 3.08 (t, J= 6.1, 2H), 2.91-2.88 (m, 4H), 1.76 (br d, 8H).
EXAMPLE 53 1 -{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyI}-4-phenyl-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 13 using 4-phenyl-piperidin-4-ol. MS (ESI): mass calculated for C26H26N204, 430.19; m/z found, 431.2 [M+H]+. 1H NMR (400 MHz, CDCi3): 7.60-7.45 (m, 15 3H), 7.40-7.18 (m, 8H), 7.00 (d, J = 9.1, 2H), 4.18 (t. J = 5.9, 2H), 2.92 (t, J = 5.9, 2H), 2.66 (dt, J= 12.1, 2.4, 2H), 2.22 (dt, J= 13.4, 4.5, 2H), 1.80 (dd, J = 14.1, 2.4, 2H). {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyciohexyl-ethyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 13 using cyclohexyl-ethyl-amine. MS (ESI): mass calculated for C23H28N2O3, 25 380.21; m/z found, 381.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.51 (d, J = 8.4, 1H), 7.42 (d, J = 7.5, 1H), 7.35-7.18 (m, 4H), 6.97 (d, J = 9.1, 2H), 3.98 (t, J = EXAMPLE 54 115 544938 6.9, 2H), 2.88 (t, J= 6.9, 2H), 2.67 (q, J= 7.1, 2H), 2.55-2.50 (m, 1H), 1.82 (t, J = 7.4, 4H), 1.64 (d, J = 12.4, 1H), 1.21 (t, J = 7.9, 4H), 1.08 (t, J = 7.1, 4H).
EXAMPLE 55 2-{4-[2-(2-Ethyl~piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole.
The title compound was prepared according to the procedure for EXAMPLE 13 using 2-ethyl-piperidine. MS (ESI): mass calculated for C22H26N2O3, 366.19; 10 m/z found, 367.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.51 (d, J = 7.4, 1H), 7.42 (d, J = 7.4, 1H), 7.31 (d, J = 9.1, 2H), 7.30-7.20 (m, 2H), 6.97 (d, J = 9.1, 2H), 4.09 (t, J= 6.4, 2H), 3.15-3.05 (m, 1H). 3.00-2.92 (m, 1H), 2.88-2.80 (m, 1H), 2.48-2.37 (m, 1H), 2.30-2.25 (m, 1H), 1.75-1.65 (m, 4H), 1.60-1.54 (m, 2H), 1.52-1.42 (m, 1H), 1.38-1.24 (m, 2H), 0.92 (t, J = 7.4, 3H). 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyI}-4-phenyl-piperidine-4-carbonitrile.
The title compound was prepared according to the procedure for EXAMPLE 13 using 4-phenyl-piperidine-4-carbonitrile. MS (ESI): mass calculated for C27H25N3O5, 439.19; m/z found, 440.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.61-7.49 (m, 3H), 7.43-7.38 (m, 3H), 7.36-7.29 (m, 3H), 7.28-7.20 (ms 3H), 25 7.03-6.96 (m, 2H), 4.15 (t, J = 5.6, 2H), 3.18 (br d, 2H), 2.93 (t, J = 5.6, 2H), 2.71-2.61 (m, 2H), 2.22-2.10 (m, 8H).
EXAMPLE 56 116 544938 EXAMPLE 57 1-(1~{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyI}-4-phenyl-pipersdin-4-yl)-ethanone.
The title compound was prepared according to the procedure for EXAMPLE 13 using 1-(4-phenyl-piperidin-4-yl)-ethanone. MS (ESI): mass calculated for C28H28N204i 456.20; m/z found, 457.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.52-7.49 (m, 1H), 7.43-7.40 (m, 1H), 7.37-7.16 (m, 9H), 6.99-6.92 (m, 2H), 10 4.10 (t, J = 5.8, 2H), 2.87-2.82 (m, 2H), 2.78 (t, J = 5.8, 2H), 2.51-2.47 (m, 2H), 2.39 (br t, 2H), 2.17-2.05 (m, 2H), 1.92 (s, 3H).
EXAMPLE 58 The title compound was prepared according to the procedure for EXAMPLE 13 using 4-methyl-piperidine. MS (ESI): mass calculated for C21H24N2O3, 352.18; m/z found, 353.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.50 (d, J = 6.8, 1H), 7.42 (d, J - 6.8, 1H), 7.31 (d, J = 9.0, 2H), 7.30-7.20 (m, 2H), 6.97 (d, J = 9.0, 2H), 4.13 (t, J = 6.0, 2H), 2.97 (d, J = 11.7, 2H), 2.80 (t, J = 6,0, 2H), 2.11 (dt, J = 11.7, J = 2.2, 2H), 1.67 (s, 2H), 1.34 (br s, 1H), 1.28 (dt, J = 12.2, J = 3.4, 2H), 0.94 (d, J = 6.2, 3H). 2-{4-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazoie. 117 544938 EXAMPLE 59 CI 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy3-ethyl}-4-(4-chloro-phenyi)-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 13 using 4-(4-chloro-phenyl)-piperidin-4-ol, MS (ESI): mass calculated for C26H25C]N204) 464.15; m/z found, 465.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.54-7.42 (m, 4H), 7.37-7.31 (m, 4H), 7.29-7.21 (m, 2H), 7.03-6.98 (m, 2H), 10 4.16 (t, J = 5.8, 2H), 2.93-2.89 (m, 4H), 2.62 (dt, J = 12.2, 2.4, 2H), 2.21-2.14 (m, 2H), 1.78-1.74 (m, 2H), 1.56 (br s, 1H).
EXAMPLE 60 1 -{2-[4-(Benzooxazol-2-yloxy)-phenoxyj-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol. ^ The title compound was prepared according to the procedure for EXAMPLE 13 using 4-(4-bromo-phenyl)-piperidin-4-ol. MS (ESI): mass calculated for 20 C26H25BrN204, 508.10; m/z found, 509.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.55-7.47 (m, 3H), 7.44-7.39 (m, 3H), 7.37-7.31 (m, 2H), 7.30-7.19 (m, 2H), 7.02-6.98 (m, 2H), 4.17 (t, J = 5.7, 2H)S 2.94-2.89 (m, 4H), 2.62 (dt, J= 12.2, 2.4, 2H), 2.21-2.13 (m, 2H), 1.78-1.74 (m, 2H)t 1.56 (brs, 1H). 118 544938 EXAMPLE 61 •CI 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 13 using 4-(4-chloro-3-trifluoromethyl-phenyi)-piperidin-4-oI. MS (ESI): mass calculated for C27H24CIF3N2O4, 532.14; m/z found, 533,1 [M+H]+. 1H NMR (400 MHz, CDCIg): 7.89 (d, J = 2.1, 1H), 7,62 (dd, J = 8.4, 2.1, 1H), 7.51-7,41 (m, 10 3H), 7.33-7.21 (m, 4H), 6.99-6.95 (m, 2H), 4.14 (t, J = 5.7, 2H), 2.94-2.89 (m, 4H), 2.65-2.59 (m, 2H), 2.21-2.13 (m, 4H), 1.74 (br s, 1H).
EXAMPLE 62 1-{2-[4-(Benzooxazol-2-y!oxy)-phenoxy]-ethyi}-4-benzyl-piperidin-4-oI.
The title compound was prepared according to the procedure for EXAMPLE 13 using 4-benzy!-piperidin-4-ol. MS (ESI): mass calculated for C27H28N2O4, 444.20; m/z found, 445.1 [M+Hf. 1H NMR; (400 MHz, CDCI3) 7.53-7.50 (m, 20 1H), 7.43-7.40 (m, 1H), 7.53-7.21 (m, 10H), 7.01-6.95 (m, 2H), 4.12 (t, J = 5.9, 2H), 2.84 (t, J = 5.8, 2H), 2.78-2.76 (m, 4H), 2.47 (dt, J = 11.6, 2,4, 2H), 1.83-1.75 (m, 2H), 1.59-1.53 (m, 2H).
EXAMPLE 63 / 119 544938 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-cyclohexyl-methyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 13 using cyclohexyl-methyl-amine, MS (ESI): mass calculated for 022^6^03, 5 366.19; m/z found, 367.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.62 (dd, J = 6.2, J = 2.0, 1H), 7.50 (dd, J = 6.1, 2.1, 1H), 7.42 (d, J = 9,1, 2H), 7.35-7.25 (m, 2H), 7.03 (d, J = 9.1, 2H), 4.04 (t, J = 6.1, 2H), 2.79 (t, J = 6.1, 2H), 2.45-2.32 (m, 1H), 1.73 (d, J = 7.9, 4H), 1.57 (d, J = 12.2, 2H), 1.30-1.12 (m, 4H), 1.10-1.00 (m, 1H).
EXAMPLE 64 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclopropylmethyi-propyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 13 using cyclopropylmethyl-propyl-amine. MS (ESI): mass calculated for c22h26n2o3, 366.19; m/z found, 367.3 [M+h]\ 1h NMR (400 MHz, CDCi3): 7.52-7.50 (m, 1H), 7.44-7.41 (m, 1H), 7.33-7.21 (m, 4H), 6.99-6.95 (m, 2H), 4.09 (t, J = 6.2, 2H), 3.01 (t, J = 6.2, 2H), 2.64-2.59 (m, 2H), 2.49 (d, J =j 6.3, 20 2H), 1.60-1.50 (m, 2H), 0.92 (t, J= 7.3, 4H), 0.55-0.52 (m, 2H), 0.16-0.13 (m, 2H).
EXAMPLE 65 {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-butyl-ethyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 13 using butyl-ethyl-amine. MS (ESI): mass calculated for 021^6^03, 354.19; 120 544938 m/z found, 355.2 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.41 (d, J = 7.2, 1H), 7.32 (dd, J = 7.3, 1.6, 1H), 7.22 (d, J = 9.1, 1H), 7.18-7.10 (m, 2H), 6.87 (d, J = 9.1, 2H), 4.02 (br s, 2H), 2.85 (br s, 2H), 2.61 (br s, 2H), 2.49 (br s, 2H), 1.42 (brs, 2H), 1.31-1.19 (m, 2H), 1.05 (brs, 3H), 0.83 (t, J = 7.3, 3H).
EXAMPLE 66 2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-benzyi-amino)-ethano].
The title compound was prepared according to the procedure for EXAMPLE 13 using benzylamino-ethanol. MS (ESI): mass calculated for C24H24N2O4, 404.17; m/z found, 405.2 [M+H]+. 1H NMR (400 MHz, cd3od): 7.46-7,37(m, 3H), 7.33 (d, J = 16.9, 2H), 7.29-7.00 (m, 6H), 6.95 EXAMPLE 67 The title compound was prepared according to the procedure for EXAMPLE 13 using 4-benzyl-piperidine. MS (ESI): mass calculated for 027^8^03, 428.21; m/z found, 429.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.53-7.50 (m, 1H), 7.44-7.41 (m, 1H), 7.33-7.15 (m, 9H), 6.98-6.95 (m, 2H), 4.11 (t, J = 6.0, 2H), 3.01-25 2.96 (m, 2H), 2.79 (t, J = 6.0, 2H), 2.55 (d, J = 7.0, 2H)t 2.09-2.02 (m, 2H), 1.67-1.64 (m, 2H), 1.59-1.51 (m, 1H) 1.40-1.29 (m, 2H). 2-{4-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole. 121 544338 EXAMPLE 68 ■OH (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3-yl)-methanoI.
The title compound was prepared according to the procedure for EXAMPLE 13 using piperidin-3-y[-methanol. MS (ESI): mass calculated for C2iH24N204, 368.17; m/z found, 369.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.55-7.52 (m, 1H), 7.48-7.44 (m, 1H), 7.38-7.23 (m, 4H), 7.05-6.99 (m, 2H), 4.23 (t, J= 5.6, 2H), 3.71 (dd, J=10.7, 5.1, 1H),3.59 (dd, J = 10.6, 6.4, 1H), 3.09 (brd,J = 10 9.7, 1H), 2.94 (t, J = 5.6, 2H), 2.42 (t, J = 9.1, 1H), 2.29 (t, J = 9.3, 1H), 2.24-1.98 (m, 2H), 2.00-1.90 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.71 (m, 2H), 1.20-1.10 (m,1H).
EXAMPLE 69 2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-propyl-amino)-ethanol.
The title compound was prepared according to the procedure for EXAMPLE 13 using 2-propylamino-ethanol. MS (ESI): mass calculated for C20H24N2O4, 20 356.17; m/z found, 357.3 [M+Hf. 1H NMR (400 MHz, DMSO -c/6): 7.62 (dd, J = 6.2, 2.0, 1H), 7.50 (dd, J = 6.1, 2.1, 1H), 7.42 (d, J = 9.1, 2H), 7.35-7.25 (m, 2H), 7.03 (d, J = 9.1, 2H), 4.31 (t, J = 5.4, 1H), 4.04 (t, J = 6.0, 2H), 3.46 (q, J = 6.4, 2H), 2.85 (t, J = 6.0, 2H), 2.59 (t, J = 6.5, 2H), 2.51-2.48 (m, 2H), 1.41 (q, J = 7.4, 2H), 0.84 (W= 7.3, 3H). . 122 544938 EXAMPLE 70 1_{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-phenyI-piperidin-4-oI.
The title compound was prepared according to the procedure for EXAMPLE 17 using 4-phenyl-piperidin-4-ol. MS (ESI): mass calculated for C26H26N2O3S, 446.17; m/z found, 447.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8,1, 1H), 7.66 (d, J = 7.4, 1H), 7.54 (d, J= 7.6, 2H), 7.42-7.35 (m, 3H), 7.33-7.22 (m, 4H), 6.99 (d, J = 9.0, 2H), 4.19 (t, J = 5.8, 2H), 2.98-2.86 (m, 4H), 2.65 (dt, 10 J= 13.8, 2.1, 2H), 2.24 (dt, J= 13.4, 4.5, 2H), 1.80 (dd, J= 14.1, 2.2, 2H).
EXAMPLE 71 {2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine. using cyclohexyl-ethyl-amine. MS (ES!): mass calculated for C23H28N202S, 396.19; m/z found, 397.2 [M+Hf. 1H NMR (400 MHz, CDClg): 7.74 (d, J= 8,1, 1H), 7.65 (d, J = 7.9, 1H), 7.39 (t, J = 7,9, 4H), 7.30-7.20 (m, 4H), 6.96 (d, J = 20 8.9, 2H), 3.98 (t, J = 6.8, 2H), 2.89 (t, J = 6.8, 2H), 2.66 (q, J = 7,1, 2H), 2.55-2.50 (m, 1H), 1.82 (t, J = 7.7, 4H), 1.65 (d, J=11.9, 1H), 1.30-1.18 (m, 4H), 1.09 (t, J = 7.2, 4H).
The title compound was prepared according to the procedure for EXAMPLE 17 123 544938 EXAMPLE 72 CI 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-4-(4-chIoro-phenyl)-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 17 using 4-(4-chloro-phenyl)-piperidin-4-ol. MS (ESI): mass calculated for C26H25CIN303S, 480.13; m/z found, 481.1 [M+H]+. 1H NMR (400 MHz, CDCfe): 7.74 (d, J = 7.6, 1H), 7.66 (66, J =7.9, 0.8, 1H), 7.49-7.45 (m, 2H), 7.41-7.22 10 (m, 6H), 7.01-6.97 (m, 2H), 4.18 (t, J = 5.8, 2H), 2.96-2.89 (m, 4H), 2.63 (dt, J = 12.1, 2.4, 2H), 2.21-2.14 (m, 2H), 1.79-1.74 (m, 2H), 1.56 (brs, 1H).
EXAMPLE 73 {2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine.
The title compound was prepared according to the procedure for EXAIv/pLE 17 using dibutyl-amine. MS (ESI): mass calculated for C23H30N2O2S, 398.20; m/z found, 399.2 [M+Hf. 1H NMR (400 MHz, GDCI3): 7.63 (d, J = 8.1, 1H), 7.55 20 (d, J = 7.9, 1H), 7.28 (tt, J = 7.7, 1.3, 1H), 7.20-7.13 (m, 3H), 6.85 (d, J = 12.8, 2H), 3.96 (t, J = 5.6, 2H), 2.80 (m, 2H), 2.43 (m, 4H), 1.38 (m, 4H), 1.22 (m, 4H), 0.83 (t, J= 7.3 Hz, 6H).
EXAMPLE 74 124 544938 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4- The title compound was prepared according to the procedure for EXAMPLE 17 5 using 4-(4-bromo-phenyl)-piperidin-4-ol. MS (ESI): mass calculated for CsehhsBrNsOaS, 524.08; m/z found, 525.1 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.74 (dd, J = 8.0, 0.6, 1H), 7.67 (dd, J = 8.0, 0.8, 1H), 7.53-7.47 (m, 2H), 7.43-7.37 (m, 3H), 7.30-7.22 (m, 3H), 7.01-6.98 (m, 2H), 4.17 (t, J= 5.8, 2H), 2.94-2.89 (m, 4H), 2.63 (dt, J = 12.1, 2.5, 2H), 2.21-2.14 (m, 2H), 1.76 (dd, J = 10 14.22.6, 2H), 1.56 (brs, 1H).
EXAMPLE 75 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-4-(4-chloro-3-trifluoromethyi-15 phenyl)-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 17 using 4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-oI. MS (ESI): rriE^s calculated for Ci^CIFaNaOaS, 548.11; m/z found, 549.1 [M+Hf. 1H NMR 20 (400 MHz, CDCIs): 7.89 (d, J = 2.1, 1H), 7.62-7,48 (m, 4H), 7.41-7.37 (m, 1H), 7.30-7.24 (m, 3H), 7.01-6.97 (m, 2H), 4.17 (t, J = 5.8, 2H), 2.94-2.91 (m, 6H), 2.66-2.59 (m, 2H), 2.22-2.15 (m, 2H), 1.83 (brs, 1H).
EXAMPLE 76 ol. 1-{2-[4-(Benzothiazol-2-yfoxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol. 125 544938 The title compound was prepared according to the procedure for EXAMPLE 17 using 4-benzyl-piperidin-4-ol. MS (ESI): mass calculated for C27H28N2O3S, 460.18; m/z found, 461.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.66 (d, J= 7.7, 1H), 7,41-7.23 (m, 9H), 6.99-6.94 (m, 2H), 4.13 (t, J = 5.9, 5 2H), 4.84 (t, J = 5.9, 2H), 2.78 (m, 4H), 2.50-2.45 (m, 2H), 1.83-1.76 (m, 2H), 1.59-1.52 (m, 2H), 1.23 (br s, 1H).
EXAMPLE 77 2-[4-(2-Azetidin-1 -yl-ethoxy)-phenoxy]-benzooxazo!e.
The title compound was prepared according to the procedure for EXAMPLE 21 using azetidine. MS (ESI): mass calculated for Ci8HigN203, 310.13; m/z found, 311.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.61 (d, J = 7.0, 2H), 15 7.48 (d, J = 7.0, 2H), 7.41 (d, J = 9.1, 2H), 7.32-7.24 (m, 2H), 7.00 (d, J = 6.9, 2H), 3.93 (t, J = 5.6, 2H), 3.18 (t, J = 6.9, 4H), 2.70 (t, J = 5.6, 2H), 1.97 (t, J = 6.9, 2H).
EXAMPLE 78 A/-(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-2-phenyI-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 22 using 2-phenyl-N-piperidin-4-yl-acetamide and 2-chloro-benzooxazole. MS 25 (ESI): mass calculated for Cas^gNaCU, 471.22; m/z found, 472.5 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.55-7.51 (m, 1H), 7.47-7.43 (m, 1H), 7.41-7.23 (m, 9H), 7.00-6.95 (m, 2H), 5.28 (br d, J = 7.8, 1H), 4.10 (t, J = 5.7, 2H), 3.90^3.80 H 126 544938 (m, 1H), 3.60 (s, 2H), 2.89 {br d, J = 11.5, 2H), 2.81 (t, J = 5.8, 2H), 2.28 (dt, J = 11.6, 2.2, 2H), 1.92 (br dd, J = 12,6, 2.3, 2H), 1.46-1.37 (m, 2H).
EXAMPLE 79 o 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidine-3-carboxylic acid ethyi ester.
The title compound was prepared according to the procedure for EXAMPLE 22 using piperidine-3-carboxylic acid ethyl ester and 2-chloro-benzooxazole. MS (ESI): mass calculated for C23H26N2O5, 410.18; m/z found, 411.4 [M+Hf, 1H NMR (400 MHz, CDCI3): 7.56-7.52 (m, 1H), 7.47-7.43 (m, 1H), 7.37-7,32 (m, 2H), 7.32-7.23 (m, 2H), 7.02-6.98 (m, 2H), 4.18 (q, J= 7.1, 2H), 4.15 (t, J= 5.9, 2H), 3.14 (brd, J= 8.2, 1H), 2.96-2.82 (m, 3H), 2.65 (tt, J= 10.6, 3.7, 1H), 2.37 (t, J= 10.7, 1H), 2.20 (dt, J=10.9, 2.7, 1H), 2.03-1.97 (m, 1H), 1.82-1.75 (m, 15 1H), 1.73-1.60 (m, 1H), 1.54-1.45 (m, 1H) 1.30 (t, J = 7.2, 3H).
EXAMPLE 80 1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethylH1,4']bipiperidine.
The title compound was prepared according to the procedure for EXAMPLE 22 using 4-piperidinyl-piperidine. MS (ESI): mass calculated for C25H31N3O2S, 437.21; m/z found, 438.4 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.77 (d, J= 8.0, 1H), 7.69 (d, J- 7.0, 1H), 7.42 (dt, J = 7.1, 1.1, 1H), 7.35-7.26 (m, 3H), 7.04-25 6.97 (m, 2H), 4.15 (t, J = 5.9, 2H), 3.11 (br d, J = 11.7, 2H), 2.84 (t, J = 6.0, 2H), 2.57 (br s, 2H), 2.40-2.30 (m, 1H), 2.16 (dt, J = 11.7, 1.6, 1H), 1.85 {br d, J = 12.1, 2H), 1.75-1.59 (m, 8H), 1.52-1.40 (m, 2H). 127 544938 EXAMPLE 81 {1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-yI)-methanoi, The title compound was prepared according to the procedure for EXAMPLE 17 using piperidin-4-yl-methanol. MS (ESI): mass calculated for CziHa^OsS, 384.15; m/z found, 385.1 [M+H]+. 1H NMR (500 MHz, CDC!3): 7.75-7.73 (m, 1H), 7.67-7.65 (m, 1H), 7.41-7.37 (m, 1H), 7.31-7.36 (m, 3H), 6.98-6.95 (m, 10 2H), 4.13 (t, J = 5.9, 2H), 3.52 (t, J = 5.4, 2H)S 3.10-3.03 (m, 2H), 2.83 (t, J = 5.9, 2H), 2.14 (dt, J = 11.8, 2.4, 2H), 1.78-1.75 (m, 2H), 1.58-1.52 (m, 2H), 1.37-1.30 (m,2H), EXAMPLE 82 H A/-(1-{2-[4~(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-2-phenyl-acetamide. I The title compound was prepared according to the procedure for EXAMPLE 22 20 using 2-phenyl-A/-piperidin-4-yl-acetamide. MS (ESI): mass calculated for C28H29N3O3S, 487.19; m/z found, 488.2 [M+H]+, 1H NMR (400 MHz, CDCI3): 7.78 (dd, J = 8.0, 0.6, 1H), 7.69 (dd, J = 7.9, 0.7, 1H), 7.45-7.24 (m, 9H), 7.00-6.88 (m, 2H), 5.33 (d, J= 7.9, 1H), 4.10 (t, J = 5.8, 2H), 3.90-3.79 (m, 1H), 3.60 (s, 2H), 2.88 (d, J = 11.7, 2H), 2.80 (t, J = 5.7, 2H), 2.27 (dt, J = 11.6, 2.2, 2H), 25 1.92 (dd, J = 12.7, 3.6, 2H), 1.39 (dq, J = 11.1, 3.8, 2H). 128 544938 EXAMPLE 83 1'-{2-[4-(Benzothiazol-2-yIoxy)-phenoxy]-ethyIH1,4']bipiperidinyl-2-one.
The title compound was prepared according to the procedure for EXAMPLE 22 using [1,4']bipiperidinyl-2-one. MS (ESI): mass calculated for C25H29N3O3S, 451.59; m/z found, 452.4 [M+Hf. 1H NMR (400 MHz, DMSOcfe): 7.91 (d, J = 7.4, 1H), 7.67 (d, J = 7.4, 1H), 7.45-7.32 (m, 4H), 7.06 (d, J- 9.0, 2H), 4.35-4.15 (m, 1H), 4.10 (t, J = 5.7, 2H), 3.15 (t,J = 5.3, 2H), 3.00 (d, J = 11.5, 2H), 10 2.71 (t, J = 5.7, 2H), 2.21 (t, J = 6.5, 2H), 2.10 (t, J = 11.5, 2H), 1.75-1.60 (m, 6H), 1.43 (d, J= 10.0, 2H).
EXAMPLE 84 2-(4-{2~[4-{2-Morpholin-4-yl-ethyl)-piperazin-1 -yl]-ethoxy}-phenoxy}-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 22 using 4-(2-piperazin-1-yl-ethyl)-morpholine. MS (ESI): mass calculated for 20 C25H32N4O3S, 468.22; m/z found, 469.2 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.91 (d, J = 7.9, 1H), 7.67 (d, J = 7.9, 1H), 7.45-7.32 (m, 4H), 7.06 (d, J = 9.1, 2H), 4.09 (t, J = 5.8, 2H), 3.54 (t, J = 4.6, 2H), 2.68 (t, J = 5.7, 2H), 2.50-2.20 (brs, 16H). 129 544938 EXAMPLE 85 i | 2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yI]-ethyl}-phenoxy)-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 32 using 4-(2-piperazin-1-yl-ethyl)-morpholine, MS (ESI): mass calculated for C25H32N402S, 452.22; m/z found, 453.2 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.92 (d, J = 8.0, 1H), 7.68 (d, J = 8.0, 1H), 7.45-7.30 (m, 6H), 3.54 (t, J = 10 4.5, 4H), 2.75 (t, J = 8.3, 4H), 2.50-2.20 (br s, 16H).
EXAMPLE 86 2-{4-[3-(4-Phenyl-piperidin-1-yl)-propoxy]-phenoxy}-benzooxazoIe. j The title compound was prepared according to the procedure for EXAMPLE 27 using 4-phenyl-piperidine. MS (ESI): mass calculated for C27H28N203, 428.21; m/z found, 429.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.40-7.38 (m, 1H), 7.34-7.32 (m, 1H), 7.24 (d, J = 9.1, 2H), 7.22-7.12 (m, 4H), 7.07 (t, J- 7.0, 1H), 20 6.94 (d, J = 9.1, 2H), 3.99 (t, J = 6.1, 2H), 3.06 (d, J = 11.7, 2H), 2.57 (t, J = 7.6, 2H), 2.49 (m, 1H), 2.13 (t, J = 11.6, 2H), 1.97 (m, 2H), 1.73 (m, 4H). 130 544938 EXAMPLE 87 1-{3-[4-(Benzothiazo[-2-yloxy)-phenoxy]-propyI}-4-phenyl-piperidin-4-ol, The title compound was prepared according to the procedure for EXAMPLE 27 using 2-chlorobenzothiazole. MS (ESI); mass calculated for C27H28N2O3S, 460.18; m/z found, 461.2 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.65 (d, J = 7.8, 1H), 7.53 (d, J = 8.2, 2H), 7.39-7.35 (m, 3H), 7.29-7,23 (m, 5H), 6.96 (d, J = 9.1, 2H), 4.08 (t, J = 6.2, 2H), 2.92 (m, 2H), 2.72-2,49 (m, 10 4H), 2.34-2.02 (m, 4H), 1.81 (d, J = 12,3, 2H).
EXAMPLE 88 The title compound was prepared according to the procedure for EXAMPLE 29 using 4-phenyl-piperidin-4-ol. MS (ESI): mass calculated for C26H26N2O3, 414.51; m/z found, 415.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7,56-7.51 (m, 3H), 7.45-7.32 (m, 6H), 7.30-7.22 (m, 4H), 2.96-2.89 (m, 2H), 2.74-2.69 (m, 20 2H), 2.61-2.54 (m, 2H), 2.26-2.18 (m, 2H), 1.84-1.79 (m, 2H), 1.62 (brs, 1H).
EXAMPLE 89 1-{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-4-phenyi-piperidin-4-ol. I 131 544938 {2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-cycIohexyl-ethy!-amine, The title compound was prepared according to the procedure for EXAMPLE 29 using cyciohexyl-ethyl-amine. MS (ESI): mass calculated for C23H28N2O2, 5 364.22; m/z found, 365.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.51 (d, J = 7.8, 1H), 7.41 (d, J= 7.6, 1H), 7.33-7.18 (m, 6H), 2.80-2,68 (m, 4H), 2.64 (dd, J~ 6.8, 7.04, 2H), 2.58-2.50 (m 1H), 1.80 (t, J = 8.8,4H), 1.63 (d, J = 12.3, 1H), 1.22 (dd, J = 9.8, 8.4, 4H), 1.08 (t, J = 7.0, 4H).
EXAMPLE 90 2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzooxazole.
The title compound was prepared according to the procedure for EXAMPLE 29 15 using pyrrolidine. MS (ESI): mass calculated for C19H20N2O2, 308.15; m/z found, 309.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.51 (d, J = 7.6, 1H), 7.42 (d, J = 7.2, 1H), 7.35-7.20 (m, 6H), 2.90-2.84 (m, 2H), 2.75-2.68 (m 2H), 2.62-2.55 (m, 4H), 1.85-1.79 (m, 4H). 2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzooxazole.
The title compound was prepared according to the procedure for EXAMPLE 29 25 using azepane. MS (ESI): mass calculated for C2iH24N202, 336.18; m/z found, 337.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.50 (d, J = 7.6, 1H), 7.39 EXAMPLE 91 132 544938 (d, J = 7.8, 1H), 7.33-7.17 (m, 6H), 2.84-2.73 (m, 4H), 2.71 (t, J = 5.3, 4H), 1.71-1.57 (m, 8H).
EXAMPLE 92 {2-[4-{Benzooxazol-2-yloxy)-pheriyl]-ethy!}-cyclopropylmethyl-propyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 29 using cyclopropylmethyl-propyl-amine. MS (ESI): mass calculated for 10 C22H26N202, 350.20; m/z found, 351.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.50 (d, J = 7.6, 1H), 7.39 (d, J = 7.8, 1H), 7.33-7.17 (m, 6H), 2.85-2.74 (m, 4H), 2.56 (t, J = 7.6, 2H), 2.43 (d, J = 6.5, 2H), 1.56-1.44 (m, 2H), 0.90 (t, J = 7.2, 4H), 0.51 (dd, J= 7.8, 5.5, 2H), 0.13 (dd, J= 7.8, 5.5, 2H).
EXAMPLE 93 {2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 29 20 using dibutyl-amine. MS (ESI): mass calculated for C23H30N2O2, 366.23; m/z found, 367.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.51 (d, J = 7.4, 1H), 7.39 (d. J = 7.6, 1H), 7.33-7.17 (m, 6H), 2.80-2.66 (m, 4H), 2.49 (t, J = 7.3, 4H), 1.50-1.40 (m, 4H), 1.37-1.26 (m, 4H), 0.93 (t, J = 7.2, 6H). 133 544338 EXAMPLE 94 OH 1-{2-[4-(Benzooxazol-2-yloxy)-phenyi]-ethyl}-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 29 using 4-hydroxypiperidine. MS (ESI): mass calculated for 020^2^03, 338.16; m/z found, 339.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.50 (d, J= 7.6, 1H), 7.39 (d, J = 7.6, 1H), 7.34-7.16 (m, 6H), 3.72-3.63 (m, 1H), 3.29 (brs, 1H), 2.91-2.78 (m, 4H), 2.63-2.56 (m, 2H), 2.21 (t, J- 10.0, 2H), 1.96-1.86 (m, 2H), 10 1.70-1.57 (m,2H).
EXAMPLE 95 The title compound was prepared according to the procedure for EXAMPLE 30 using 4-phenyl-piperidin-4-ol. MS (ESI): mass calculated for C26H26N2O3S, 430.57; m/z found, 431.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.76-7.74 (m, 1H), 7.67 (dd, J= 8.0, 0.7, 1H), 7.56-7.53 (m, 2H), 7.42-7.36 (m, 3H), 7.33-20 7.26 (m, 6H), 2.96-2.86 (m, 4H), 2.75-7.71 (m, 2H), 2.64-2.56 (m, 2H) 2.27-2.18 (m, 2H), 1.86-1.80 (m, 2H), 1.67-1.66 (br m, 2H). 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ol. 134 544938 EXAMPLE 96 o 1 -{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 29 using piperidine-4-carboxylic acid methyl ester, MS (ESI): mass calculated for C22H24N204! 380.17; m/z found, 381.4 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.50 (d, J = 8.1, 1H), 7.39 (d, J = 8.1, 1H), 7.34-7.16 (m, 6H), 3.67 (s, 3H), 10 2.97-2.90 (m, 2H), 2.84-2.78 (m, 2H), 2.60-2.55 (m, 2H), 2.35-2.25 (m, 1H), 2.10 (t, J = 11.4, 2H), 1.96-1.88 (m, 2H), 1.84-1.73 (m, 2H).
EXAMPLE 97 2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 30 using pyrrolidine. MS (ESI): mass calculated for C1gH2oN20SJ 324.13; m/z found, 325,3 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.73 (d, J = 8.0, 1H), 7.65 20 (d, J = 8.0, 1H), 7.38 (t, J = 7.2, 1H), 7,31-7.22 (m, 5H), 2.91-2.83 (m, 2H), 2.77-2.69 (m 2H), 2.64-2.55 (m, 4H), 1.87-1.77 (m, 4H).
EXAMPLE 98 135 544938 2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 30 using azepane. MS (ESI): mass calculated for C21H24N2OS, 352.16; m/z 5 found, 353.4 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.73 (d, J = 8.0, 1H), 7.65 (d, J = 8.0, 1H), 7.37 (t, J = 7.4, 1H), 7.30-7.22 (m, 5H), 2.87-2.70 (m, 8H), 1.73-1.57 (m, 8H).
EXAMPLE 99 {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-cyclopropylmethyl-propyl-amine, The title compound was prepared according to the procedure for EXAMPLE 30 using cyclopropylmethyl-propyi-amine. MS (ESI): mass calculated for 15 C22H26N20S, 366.18; m/z found, 367.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.6, 1H), 7.65 (d, J = 8.2, 1H), 7.38 (t, J = 8.6, 1H), 7.30-7.22 (m, 5H), 2.87-2.76 (m, 4H), 2.57 (t, J = 7.6, 2H), 2.44 (d, J = 6.5, 2H), 1.56-1.45 (m, 2H), 0.90 (t, J = 7.4, 4H), 0.52 (dd, J = 7.8, 5.5, 2H), 0.14 (dd, J = 5.7, 5^1, 2H).
EXAMPLE 100 {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-dibutyi-amine.
The title compound was prepared according to the procedure for EXAMPLE 30 25 using dibutyl-amine. MS (ESI): mass calculated for C23H30N2OS, 382.21; m/z found, 383.4 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.73 (d, J = 8.2,1H), 7.65 136 544938 (d, J = 8.2, 1H), 7.38 (t, J = 8.2, 1H), 7.30-7.22 (m, 5H), 2.82-2.67 (m, 4H), 2.51 (t, J = 7.2, 4H), 1.50-1.40 (m, 4H), 1.37-1.25 (m, 4H), 0.93 (t, J = 7.2, 6H).
EXAMPLE 101 2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 30 using piperidine. MS (ESI): mass calculated for C2oH22N20S, 338.48; m/z 10 found, 339.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.76-7.73 (m, 1H), 7.64-7.61 (m, 1H), 7.42-7.25 (m, 6H), 2.88-2.83 (m, 2H), 2.60-2.52 (m, 6H), 1.66-1.61 (m, 4H), 1.53-1.45 (m, 2H).
EXAMPLE 102 1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}»piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 30 using 4-hydroxypiperidine. MS (ESI): mass calculated for C20H22N2O2S, 20 354.14; m/z found, 355.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.2, 1H), 7.64 (d, J = 8.0, 1H), 7.37 (t, J = 8.2, 1H), 7.29-7.20 (m, 5H), 3.75-3.65 (m, 1H), 2.92-2.79 (m, 4H), 2.76 (brs, 1H), 2.65-2.55 (m, 2H), 2.21 (t, J= 10.0, 2H), 1.98-1.87 (m, 2H), 1.70-1.57 (m, 2H). 137 544938 EXAMPLE 103 O 1 -{2-[4-(Benzothiazol-2-yloxy)-pheny[]-ethyl}-piperidine-4-carboxylic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 30 using piperidine-4-carboxylic acid methyl ester, MS (ESi): mass calculated for C22H24N2O3S, 396.15; m/z found, 397.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.3, 1H), 7.66 (d, J = 8.3, 1H), 7.38 (t, J = 8.3, 1H), 7.29-7.23 (m, 10 5H), 3.69 (s, 3H), 3.00-2.93 (m, 2H), 2.87-2.80 (m, 2H), 2.63-2.56 (m, 2H), 2.38-2.28 (m, 1H), 2.11 (t, J = 11.1, 2H), 1.98-1.91 (m, 2H), 1.86-1.74 (m, 2H).
EXAMPLE 104 O 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid amide.
The title compound was prepared according to the procedure for EXAMPLE 31 using piperidine-4-carboxylic acid amide. MS (ESi): mass calculated for C21H23N302S, 381.15; m/z found, 382.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 20 7.78 (dd, J= 8.1, 0.4, 1H), 7.71 (dd, J = 7.9, 0.7, 1H), 7.43 (dt, J = 7.5, 2.3, 1H), 7.35-7.25 (m, 5H), 5.51 (br d, J = 26.0, 1H), 3.09 (br d, J = 11.7, 2H), 2.87, (dd, J = 8.3, 7.6, 2H), 2.65 (dd, J = 8.5, 5.4, 2H), 2.29-2.18 (m, 1H), 2.13 (t, J = 11.4.2H), 1.98 (brd,J= 11.2, 2H), 1.87-1.77 The title compound was prepared according to the procedure for EXAMPLE 31 using piperidine-3-carboxyiic acid ethyl ester. MS (ESI): mass calculated for C23H26N2O3S, 410.17; m/z found, 411.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (d, J= 8.0, 1H), 7.70 (dd, J= 7.9, 0.5, 1H), 7.42 (dt, J= 7.5, 1.3, 1H), 10 7.34-7.27 (m, 5H), 4.18 (q, J =7.1, 2H), 3.13 (brd, J = 8.8, 1H), 2.92-2.85 (m, 2H), 2.70-2.59 (m, 2H), 2.30 (t, J= 10.7, 1H), 2.13 (dt, J = 10.9, 2,7, 1H), 2,04-1.97 (m, 1H), 1.84-1.76 (m, 1H), 1.71-1.59 (m, 1H), 1.57-1.45 (m, 1H) 1.30 (t, J = 7.2, 3H).
EXAMPLE 106 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-4-phenyl-piperidine-4-carboxyiic acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 31 using 4-phenyl-piperidine-4-carboxylic acid ethyl ester. MS (ESI): mass calculated for C29H30N2O3S, 486.20; m/z found, 487.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.78 (dd, J = 8.1, 0.5, 1H), 7.70 (dd, J = 7.9, 0.7, 1H), 7.46-7.24 (m, 11H), 4.19 (q, J = 7.1, 2H), 3.06 (br d, J = 10.1, 2H), 2.96-2.90 (m, 2H), 2.75-2.64 (m, 4H), 2.35 (t, J = 11.0, 2H), 2.14, (t, J = 11.3, 2H), 1.24, (t, J = 7.3, 3H). 139 544938 EXAMPLE 107 (1-{2-[4-(Ben2othiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-acetic acid ethyl The title compound was prepared according to the procedure for EXAMPLE 31 using piperidin-4-yl~acetic acid ethy! ester. MS (ESI): mass calculated for C24H28N2O3S, 424.18; m/z found, 425.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 10 7.76 (d, J = 7.8, 1H), 7.70 (dd, J = 7.9, 0.6, 1H), 7.41 (dt, J = 7.2, 1.2, 1H), 7.36-7.27 (m, 5H), 4.18 (q, J= 5.3, 2H), 3.21 (d, J = 11.3, 2H), 3.03-2.99, (m, 2H), 2.83-2.78 (m, 2H), 2.33-2.25 (m, 4H), 2.00-1.87 (m, 1H), 1.86 (d, J = 14.3, 2H), 1.67-1.55 (m, 2H), 1.29 (t, J = 7.1, 3H).
EXAMPLE 108 1-(1-{2-[4-(Benzothiazoi-2-yloxy)-phenyl3-ethyl}~piperidin-4-yi)-1,3-dihydro-indol- 2-one.
The title compound was prepared according to the procedure for EXAMPLE 31 20 using 1-piperidin-4-yl-1,3-dihydro-indol-2-one. MS (ESI): mass calculated for CssHarNaOzS, 469.18; m/z found, 470,4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.75 (dd, J = 8.1, 0.4, 1H), 7.68 (dd, J = 7.9, 0.6, 1H), 7.40 (dt, J = 7.5, 1.2, 1H), 7.36-7.23 (m, 8H), 7.04 (dt, J = 7.3, 1.7, 1H), 4.57-4.45 (mf 1H), 3.54 (s, 2H), 3.36 (br d, J = 10.9, 2H), 3.00 (dd, J = 11.4, 6.3, 1H), 2.88 (dd, J = 8.8, 25 4.5, 2H), 2.75-2.62 (m, 2H), 2.45 (t, J= 11.5, 2H), 1,80 (dd, J= 12.3, 2.1, 2H). ester. 140 544938 EXAMPLE 109 1-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-yl)-pyrrolidin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 31 using 1-piperidin-4-yl-pyrrolidin-2-one. MS (ESI): mass calculated for C24H27N3O2S, 421.18; m/z found, 422.4 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.76 (d, J = 8.0, 1H), 7.69 (dd, J = 8.0, 0.9, 1H), 7.41 (dt, J = 7.5, 1.2, 1H), 7.32-7.27 (m, 5H), 4.05 (dt, J = 11.9, 4.5, 1H), 3.40 (t, J = 7.0, 2H), 3.10 (br d, 10 J = 11.7, 2H), 2.86 (dd, J = 11.0, 7.7, 2H), 2.66 (dd, J = 8.8, 5.3, 2H), 2.43 (t, J = 8.1, 2H), 2.19 (dt, J= 11.6, 2.8, 2H), 2.09-2.00 (m, 2H), 1.85-1.69 (m, 4H).
EXAMPLE 110 H A/-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-y!)-2-phenyi-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 31 using 2-phenyl-A/-piperidin-4-yl-acetamide. MS (ESI): mass calculated for 20 C28H29N3O2S, 471.20; m/z found, 472.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd J = 8.1, 0.5, 1H), 7.70 (dd, J = 7.8, 0.7, 1H), 7.45-7.37 (m, 3H), 7.36-7.26 (m, 8H), 5.39 (br d, J = 7.9, 1H), 3.93-3.82 (m, 1H), 3.60 (s, 2H), 2.93 (br d, J = 11.1, 2H), 2.86 (dd, J = 10.9, 7.6, 2H), 2.65 (dd, J - 8.5, 5.2, 2H), 2.25 (t, J = 11.2, 2H), 1.95 (dd, J - 12.8, 3.3, 2H), 1.47 (m, 2H). 141 544938 EXAMPLE 111 8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,8-diaza-spiro[4.5]decan-1-one, The title compound was prepared according to the procedure for EXAMPLE 31 using 2,8-diaza-spiro[4.5]decan-1-one. MS (ESI): mass calculated for C23H25N3O2S, 407.17; m/z found, 408.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.78 (d, J= 8.1, 1H), 7.70 (dd, J=7.8, 0.6, 1H), 7.42 (dt, J = 7.6, 1.3, 1H), 7.35-7.26 (m, 5H), 6.40 (br s, 1H), 3.40 (t, J = 6.9, 2H), 3.00 (dt, J = 11.6, 3.6, 10 2H), 2.88 (dd, J = 10.3, 7.4, 2H), 2.67 (dd, J = 8.5, 5.7, 2H), 2.23 (t, J = 10.7, 2H), 2.10-2.00 (m, 4H), 1.52 (br d, J = 13.1, 2H).
EXAMPLE 112 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-ol.
/ The title compound was prepared according to the procedure for EXAMPLE 31 using 3-hydroxypiperidine. MS (ESI): mass calculated for C2oH22N202S, 354.14; m/z found, 355.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (d, J = 7.6, 20 1H), 7.70 (dd, J - 8.0, 0.8, 1H), 7.42 (dt, J = 7.5, 1.2, 1H), 7.35-7.28 (m, 5H), 3.89 (m, 1H), 2.89 (dd, J = 10.1, 7.3, 2H), 2.71-2.65 (m, 2H), 2.64-2.54 (m, 2H), 2.53-2.36 (m, 3H), 1.92-1.80 (m, 1H), 1.74-1.55 (m, 3H). 142 544938 EXAMPLE 113 o 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidine-4-carboxylic acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 31 using piperidine-3-carboxylic acid ethyl ester. MS (ESI); mass calculated for C23H26N2O3S, 410.17; m/z found, 411.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (d, J = 8.0, 1H), 7.69 (dd, J = 7.9, 0.7, 1H), 7.41 (dt, J = 7.5, 1.2, 1H), 10 7.32-7.27 (m, 5H), 4.18 (q, J = 7.1, 2H), 3.00 (br d, J = 11.5, 2H), 2.88 (dd, J = 10.9, 7.7, 2H), 2.64 (dd, J = 8.5, 5.3, 2H), 2.35 (tt, J = 10.9, 4.3, 1H), 2.14, (t, J = 10.9, 2H), 2.02-1.94 (m, 2H), 1.90-1.78 (m, 2H), 1.30 (t, J = 7.3, 3H).
EXAMPLE 114 r-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-[1,4']bipiperidine.
The title compound was prepared according to the procedure for EXAMPLE 31 using 4-piperidinyi-piperidine. MS (ESI): mass calculated for C25H31N3OS, 20. 421.22; m/z found, 422.4 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.75 (d, J = 7.8, 1H), 7.69 (dd, J = 7.8, 0.6, 1H), 7.41 (dt, J = 7.6, 1.2, 1H), 7,33-7.25 (m, 5H), 3.15 (br d, J = 11.6, 2H), 2.90-2.70 (m, 7H) 2.65 (dd, J = 8.5, 5.3, 2H), 2,18-2.06 (m, 4H), 1.99-1.87 (m, 4H), 1.85-1.75 (m, 2H), 1.64-1.56 (m, 2H). 143 544938 EXAMPLE 115 „Ya WN .
'N\ 2-{4-[2-(4-Methyl-piperazin-1-yl)-ethy!3-phenoxy}-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 32 using 1-methyl-piperazine. MS (ESI): mass calculated for C20H23N3OS, 353.16; m/z found, 354.1 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.77 (d, J = 8.01, 1H), 7.64 (d, J= 8.1, 1H), 7.41 (t, J = 8.2, 1H), 7.37 (d, J = 8.6, 2H), 7.32-7.28 (m, 3H), 2.81-2.35 (m, 8H), 2.87 (m, 2H), 2.65 (mf 2H), 2.30 (s, 3H).
EXAMPLE 116 1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyf}-4-phenyl-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 35 using 4-phenyl-piperidin-4-ol. MS (ESI): mass calculated for 027^8^(^3, 428.21; m/z found, 429.3 [M+Hf. 1H NMR (400 MHz, DMSOofe): 7.48 (d, J = 8.4, 1H), 7.45 (m, 11H), 7.19 (t, J = 8.3, 1H), 4.76 (s, 1H), 2.66 (t, J = 7.6, 4H), 2.45 (m, 4H), 1.92 (t, J = 7.1, 2H), 1.78 (t, J = 7.1, 2H), 1.58 (d, J = 12.3, 2H).
EXAMPLE 117 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol. 144 544938 The title compound was prepared according to the procedure for EXAMPLE 37 using 4-(4-bromo-phenyl)-piperidin-4-oI. MS (ESI): mass calculated for C26H26BrN303, 507.12; m/z found, 508.2 [Mh-H]+, 1H NMR (400 MHz, CDCI3): 5 7.43-7.07 (m, 10H), 6.94-6.89 (m, 2H), 4.11 (t, J = 5.8t 2H), 2.87-2.83 (m, 4H), 2.65-2.58 (m, 2H), 2.13-2.05 (m, 2H), 1.75-1.68 (m, 2H).
EXAMPLE 118 1 -{2-[4-(1 H-Benzoimidazol-2-yloxy)-phenoxy]-ethyI}-4-(4-chloro-phenyl)-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 37 using 4-(4-chloro-phenyl)-piperidin-4-o[. MS (ESI): mass calculated for 15 C26H26CIN303j 463.17; m/z found, 464.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.38-7.22 (m, 6H), 7.17-7.12 (m, 2H), 7.09-7.04 (m, 2H), 6.91-6.81 (m, 2H), 4.08 (t, J - 5.6, 2H), 2.84-2.80 (m, 4H), 2.62 (t, J = 11.8, 2H), 2.09-2.02 (m, 2H), 1.70-1.65 (m, 2H).
EXAMPLE 119 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyI}-4-benzyi-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 37 25 using 4-benzyl-piperidin-4-ol. MS (ESI): mass calculated for C27H29N303, 443.22; m/z found, 444.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7,53 (br s, 1H), H 145 544938 7.34-7.24 (m, 4H), 7.26-7.16 (m, 7H), 6.91-6.85 (m, 2H), 4.08 (t, J= 5.8, 2H), 2.85-2.77 (m, 6H), 2.48 (dt, J = 2.5, 11.7, 2H), 1.84-1.76 (m, 2H), 1.56 (m, 2H).
EXAMPLE 120 2-[4-(3-Piperidin-1-yl-propyl)-phenoxy]-benzooxazoie, The title compound was prepared according to the procedure for EXAMPLE 35 using piperidine. MS (ESI): mass calculated for C2iH24N202, 336.18; m/z 10 found, 337.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.62 (dd, J = 5.7, 2.1, 1H), 7.50 (dd, J= 6.1, 2.1, 1H), 7.45-7.35 (m, 2H), 7.35-7.25 (m, 4H), 2.62 (t, J = 7.6, 2H), 2.30 (s, 4H), 2.25 (t, J- 7.4, 2H), 1.80-1.70 (m, 2H), 1.55-1.45 (m, 4H), 1.42-1.35 (m,2H).
EXAMPLE 121 {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-dibutyl-amine. j The title compound was prepared according to the procedure for EXAMPLE 35 20 using dibutyi-amine. MS (ESI): mass calculated for C24H32N2O2, 380.25; m/z found, 381.3 [M+Hf. 1H NMR (400 MHz, DMSO-de): 7.63 (dd, J= 6.1, 2.1, 1H), 7.50 (dd, J = 6.1, 2.1, 1H), 7.40 (d, J = 8.6, 2H)S 2.63 (t, J = 7.7, 2H), 2.50-2.30 (m, 6H), 1.70 (quint, J = 7.2, 2H), 1.40-1.20 (m, 8H), 0.88 (t, J = 7.1, 6H).
EXAMPLE 122 {3-[4~(Benzooxazol-2-yloxy)-phenyl]-propy!}-cyclopropyimethyi-propyi-amine. 146 544938 The title compound was prepared according to the procedure for EXAMPLE 35 using cyclopropylmethyl-propyl-amine. MS (ESi): mass calculated for C23H28N202) 364.22; m/z found, 365.3 [M+Hf. 1H NMR (400 MHz, DMSO-afe): 5 7.63 (d, J = 8.6, 1H), 7.40 (d, J = 8.6, 1H), 7.32 (d, J = 8.5, 2H), 7.30-7.25 (m, 4H), 2.63 (t, J = 7.6, 2H), 2.41 (t, J = 7.2, 2H), 2.28 (d, J = 6.3, 2H), 1.71 (quint, J = 7.2, 2H), 1.38 (q, J = 7.2, 2H), 0.85 (t, J = 7.3, 2H), 0.88-0.77 (m, 2H), 0.42 (d, J = 4.2, 2H), 0.05 (d, J = 4.8, 2H).
EXAMPLE 123 H {2-[4-(1H-Benzoimidazol-2-yioxy)-phenyi]-ethyl}-cyclohexyl-ethyI-amine.
The titie compound was prepared according to the procedure for EXAMPLE 38 15 using cyclohexyl-ethyl-amine. MS (ESI): mass calculated for 023^9^0, 363.23; m/z found, 364.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 11.44 (br s, 1H), 7.43-7.33 (m, 2H), 7.13-7.05 (m, 6H), 3.17 (t, J= 11.7, 1H), 3.10 (dd, J = 7.0, 7.0, 2H), 2.99-2.83 (m, 4H), 2.06 (d, J =9.8, 2H), 1.89 (d, J = 12.5, 2H), 1.69 (d, J= 12.5, 1H), 1.49-1.22 (m, 7H), 1.19-1.05 (m, 1H).
. EXAMPLE 124 H 2-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenoxy]-1 H-benzoimidazole.
The title compound was prepared according to the procedure for EXAMPLE 38 using pyrrolidine, MS (ESI): mass calculated for CigHaiNsO, 307.17; m/z ■ 147 544938 found, 308.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.35-7.22 (m, 2H), 7.14-7.04 (m, 6H), 2.79-2.72 (m, 2H), 2.67-2.57 (m, 6H), 1.87-1.77 (m, 4H).
EXAMPLE 125 2-[4-(2-Azepan-1 -yl-ethyl)-phenoxy]-1 H-benzoimidazole.
The title compound was prepared according to the procedure for EXAMPLE 38 using azepane. MS (ESI): mass calculated for C21H25N3O, 335.20; m/z found, 10 336.4 [M+H]+, 1H NMR (400 MHz, CDCI3): 7.38 (dd, J= 3.1, 2.7, 2H), 7.11 (dd, J = 3.1, 2.9, 2H), 7.10-7.00 (m, 4H), 3.25-3.15 (m, 4H), 3.06 (dd, J = 6.3, 5.3, 2H), 2.93 (dd, J = 6.1, 4.3, 2H), 2.00-1.91 (m, 4H), 1.75-1.67 (m, 4H).
EXAMPLE 126 {2-[4-(1H-Benzoimidazol-2-yioxy)-phenyl]-ethyI}-dibutyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 38 using dibutyl-amine. MS (ESI): mass calculated for C23H31N3O, 365.25; m/z 20 found, 366.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.40-7.29 (m, 2H), 7.17-7.06 (m, 6H), 2.83-2.60 (m, 8H), 1.59-1.47 (m, 4H), 1.38-1.26 (m, 4H), 0.93 (t, J = 7.2, 6H).
H H 148 544938 EXAMPLE 127 H OH 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidin-4~ol.
The title compound was prepared according to the procedure for EXAMPLE 38 using 4-hydroxypiperidine. MS (ESI): mass calculated for C20H23N3O2, 337.18; m/z found, 338.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 11.70 (br s, 1H), 7.50-7.44 (m, 1H), 7.33-7.27 (m, 1H), 7.24 (brs, 4H), 7.14-7.07 (m, 2H), 3.93 (brs, 1H), 3.68-3.58 (m, 1H), 2.97-2.75 (m, 4H), 2.63-2.52 (m, 2H), 2.19 (t, J = 9.8, 10 2H), 1.94-1.84 (m, 2H), 1.65-1.54 (m, 2H).
EXAMPLE 128 o 1 -{2-[4-(1 W-Benzoimidazol-2-yioxy)-phenyl]-ethyi}-piperidine-4-carboxyli^ acid 15 methyl ester.
The titie compound was prepared according to the procedure for EXAMPLE 38 using piperidine-4-carboxylic acid methyi ester. MS (ESI): mass calculated for C22H25N3O3, 379.19; m/z found, 380.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 20 11.76 (br s, 1H), 7.50-7.44 (m, 1H), 7.24-7.06 (m, 7H), 3.68 (s, 3H), 3.00-2.92 (m, 2H), 2.77-2.70 (m, 2H), 2.53-2.46 (m, 2H), 2.38-2.28 (m, 1H), 2.10 (t, J = 11.1, 2H), 1.98-1.90 (m, 2H), 1.86-1.74 (m, 2H).
H 149 544938 EXAMPLE 129 {2-[4-(1H-Benzoimidazol-2-yioxy)-phenoxy]~ethyl}-cycIohexyl-ethyI-amine.
The title compound was prepared according to the procedure for EXAMPLE 37 using cyclohexyl-ethyl-amine. MS (ESI): mass calculated for C23H29N3O2, 379.23; m/z found, 380.3 [M+H]+. 1H NMR (400 MHz, DMSO-ofe): 12.23 (s, 1H), 7.34-7.25 (m, 4H), 7.07 (d, J ~ 3.5, 2H), 6.98 (d, J = 9.0, 2H), 3.94 (t, J = 6.4, 2H), 2.80 (t, J = 6.4, 2H), 2.57 (d, J = 7.1, 2H), 2.50 (s, 2H), 1.72 (d, J = 10 7.8, 2H), 1.55 (s, 1H), 1.20 (t, J - 9.0, 4H), 0.99 (t J = 7.1, 3H).
EXAMPLE 130 H 2-{4-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-1 H-benzoimidazole, The title compound was prepared according to the procedure for EXAMPLE 35 using 4-methyl-piperidine, MS (ESI): mass calculated for C21H25N3O2, 351.19; m/z found, 352.3 [M+H]+. 1H NMR (400 MHz, DMSO-ofe): 12.30 (s, 1H), 7.34-7.25 (m, 4H), 7.08 (d, J = 3.8, 2H), 6.99 (d, J = 9.0, 2H), 4.08 (t, J = 5.8, 2H), 20 2.89 (d, J = 11.4, 2H), 2.67 (t, J = 5.8, 2H), 2.00 (t, J - 11.4, 2H), 1.56 (d, J = 11.5, 2H), 1.36-1.25 (m, 1H), 1.21-1.08 (m, 2H), 0.88 (d, J = 6.4, 3H).
EXAMPLE 131 H 150 544938 PCT/US20G4/024309 2-{4-[2-(2-Ethyi-piperidin-1~yl)-ethoxy]-phenoxy}-1 H-benzoimidazole.
The title compound was prepared according to the procedure for EXAMPLE 37 using 2-ethyl-piperidine. MS (ESI): mass calculated for C22H27N3O2, 365.21; 5 m/z found, 366.3 [M+H]+. 1H NMR (400 MHz, DMSO-c/6): 12.28 (s, 1H), 7.32-7.25 (m, 4H), 7.08 (d, J = 3.8, 2H), 6.99 (d, J - 8.4, 2H), 4.05 (t, J = 6.1, 2H), 3.00-2.92 (m, 1H), 2.91-2.85 (m, 1H), 2.72-2.64 (m, 1H), 2.38-2.20 (m, 2H), 1.67-1.36 (m, 6H), 1.35-1.19 (m, 2H), 0.84 (t, J= 7.5, 3H).
EXAMPLE 132 2-[4-(2-Piperidin-1 -yl-ethoxy)-phenoxy]-1 H-benzoimidazole.
The title compound was prepared according to the procedure for EXAMPLE 37 using piperidine. MS (ESI): mass calculated for C20H23N3O2, 337.18; m/z found, 338.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 12.25 (brs, 1H), 7.35-7.25 (m, 4H), 7.10-7.00 (m, 2H), 6.99 (d, J = 9.0, 2H), 4.07 (t, J = 5.9T 2H), 2,79 (t, J = 5.9, 2H), 2.43 (s, 4H), 1.55-1.45 (m, 4H), 1.38 (s, 2H). (1-{2-[4-(1H-Benzoimidazol-2-yioxy)-phenoxy]-ethyl}-piperidin-4-yl)-methanol.
The title compound was prepared according to the procedure for EXAMPLE 35 25 using piperidin-4-yi-methanol. MS (ESI): mass calculated for C21H25N3O3, 367.19; m/z found, 368.4 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 12.24 (s, 1H), 7.35-7.25 (m, 4H), 7.01 (s, 2H), 6.99 (d, J = 7.1, 2H), 4.40 (s, 1H), 4.10 (t, H EXAMPLE 133 H 151 544938 PCT/US2O04/0243O9 J = 5.7, 2H), 3.25 (t, J = 5.4, 2H), 2.93 (d, J = 11.1, 2H), 2.67 (t, J = 5.6, 2H), 1.98 (t, J = 11.6, 2H), 1.63 (d, J = 11.6, 2H), 1.28 (s, 1H), 1.12 (d, J = 9.1, 2H).
EXAMPLE 134 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol, The title compound was prepared according to the procedure for EXAMPLE 37 using 4-hydroxypiperidine. MS (ESI): mass calculated for 020^3^03, 353.17; 10 m/z found, 354.4 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 12.24 (s, 1H), 7,35-7.25 (m, 4H), 7.07 (d, J = 9.0, 2H), 6.99 (d, J = 9.0, 2H), 4.40 (s, 1H), 4.08 (t, J = 5.8, 2H), 2.53 (s, 1H), 2.78 (d, J = 11.2, 2H), 2,66 (t, J = 5.8, 2H), 2.12 (t, J = 10.3, 2H), 1.70 (d, J = 9.1, 2H), 1.38 (d, .7 = 9.9, 2H).
EXAMPLE 135 1-[4-(Benzooxazol-2-yloxy)-phenoxy]-3-pyrrolidin-1-yl-propan-2-oi.
The title compound was prepared according to the procedure for EXAMPLE 40 using pyrrolidine. MS (ESI): mass calculated for C2oH22N204! 354.16; m/z found, 355.2 [M+Hf. 1H NMR (400 MHz, DMSO-cf6): 7.62 (dd, J~ 6.2, 2.0, 1H), 7.50 (dd, J= 6.1, 2.1, 1H), 7.42 (d, J= 9.1, 2H), 7.35-7.25 (m, 2H), 7.03 (d, J = 9.1, 2H), 4.91 (d, J = 4.5, 1H), 4.05-4.00 (m, 1H), 4.00-3.85 (m, 2H), 2.70 (m, 1H), 2.50-2.40 (m, 5H), 1.68 (s, 4H).
H 152 544938 EXAMPLE 136 1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyi]-4-phenyi-piperidin-4-ol, The title compound was prepared according to the procedure for EXAMPLE 41 using 4-phenyl-piperidin-4-ol. MS (ESi); mass calculated for 027^8^03, 428.21; m/z found, 429.2 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.62-7.58 (m, 1H), 7.54-7.45 (m, 3H), 7.33-7.25 (m, 6H), 7.20-7.15 (m, 1H), 6.91 (d, J= 8.6, 2H), 4.20 (s, 2H), 4.13 (t, J = 5.5, 2H), 2.87 (m, 4H), 2.66 (t, J = 11.4, 2H), 2.13 10 (dt, J = 12.8, 3.6, 2H), 1.72 (d, J = 12.6, 2H).
EXAMPLE 137 1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyi]-piperidine-4-carboxyiic acid 15 amide.
The title compound was prepared according to the procedure for EXAMPLE 41 using piperidine-4-carboxylic acid amide. MS (ESI): mass calculated for C22H25N3O3, 379.19; m/z found, 380.4 [M+Hf. nH NMR (400 MHz, CD3OD): 7.64-7.60 (m, 1H), 7.56-7.52 (m, 1H), 7.36-7.31 (m, 2H), 7.28 (d, J- 8.7, 2H), 6.92 (d, J = 8.7, 2H), 4.22 (s, 2H), 4.11 (t, J= 5.6, 2H), 3.07 (d, J= 12.0, 2H), 2.79 (t, J= 5.6, 2H), 2.18-2.15 (m, 3H), 1.80-1.70 (m, 4H).
EXAMPLE 138 O H 153 544938 2-[4-(2-Azepan-1-yl-ethoxy)~phenoxy]-1 H-benzoimidazole amide.
The title compound was prepared according to the procedure for EXAMPLE 11 steps A and B and EXAMPLE 37 steps B and C using 1-(2-chIoro-ethyl)-5 azepane hydrochloride. MS (ESI): mass calculated for C21H25N3O2, 351.19; m/z found, 352.3 [M+H]+.. 1H NMR (400 MHz, DMSO-cfe): 12.28 (s, 1H), 7.35-7.25 (m, 4H), 7.07 (d, J- 9.1, 2H), 7.00 (d, J= 9.1, 2H), 4.05 (t, J= 6.0, 2H), 2.86 (t, J = 6.0, 2H), 2.70 (t, J = 5.1, 4H), 1.65-1.50 (m, 8H).
EXAMPLE 139 H {3-[4-(1H-Benzoimidazol-2-yioxy)-phenoxy]-propyl}-dimethy!-amine.
The title compound was prepared according to the procedure for EXAMPLE 11 15 steps A and B and EXAMPLE 37 steps B and C using (2-chloro-propyi)-dimethyl-amine hydrochloride. MS (ESI): mass calculated for C-ss^iNsC^, 311.16; m/z found, 312.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.32-7.23 (mt 2H), 7.21-7.14 (m, 4H), 6.89-6.83 (m, 2H), 3.99-3.91 (m, 2H), 2.51 (t, J = 7.2, 2H), 2.31 (s, 6H) 2.02-1.95 (m, 2H). ■ EXAMPLE 140 H 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-1 H-benzoimidazole.
The title compound was prepared according to the procedure for EXAMPLE 21 steps A and B and EXAMPLE 35 steps B and C using pyrrolidine. MS (ESI): mass calculated for C19H21N3O2, 323.16; m/z found, 324.2 [M+Hf. 1H NMR 154 544938 (400 MHz, CDCIs): 7.27 (br s, 2H), 7.15(6, J = 9.1, 4H), 6.81 (d, J = 6.8, 2H}, 4.16 (t, J = 5.5, 2H), 3.05 (t, J = 5.5, 2H), 2.86 (br s, 4H), 1.92 (br s, 4H).
EXAMPLE 141 H {2-[4-(1H-Benzoimidazol-2-yioxy)-phenoxy]-ethyl}-diethyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 21 steps A and B and EXAMPLE 35 steps B and C using diethylamine. MS (ESI): 10 mass calculated for C-igH23N302, 325.18; m/z found, 326.3 [M+H]+. 1H NMR (400 MHz, CDCb): 7.29 (br s, 2H), 7.18 (d, J = 9.0, 2H), 7.10-7.05 (m, 2H), 6.98 (d, J - 9.0, 2H), 4.03 (t, J = 6.2, 2H), 2.78 (t, J = 6.1, 2H), 2.55 (q, J = 7.1, 4H), 0.98 (t, J = 7.1, 6H).
EXAMPLE 142 H 2-[4-(2-Morpholin-4-yl~ethoxy)-phenoxy]-1 H-benzoimidazole.
The title compound was prepared according to the procedure for EXAMPLE 21 20 steps A and B and EXAMPLE 37 steps B and C using morpholine. MS (ESI): mass calculated for C19H21N3O3, 339.16; m/z found, 340.2 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 7.40-7.25 (m, 4H), 7.12-7.08 (m, 2H), 7.00 (d, J = 9.0, 2H), 4.10 (t, J = 5.7, 2H), 3.58 (t, J = 4.5, 4H), 2.70 (t, J = 5.7, 2H), 2.52-2.46 (m, 4H).
EXAMPLES 143-202 and 204-229 Compounds of this invention that are referred to herein for which no explicit preparation description is provided can be prepared according to procedures 155 544938 analogous to those described herein in light of the knowledge of one of ordinary skill in the art and the teachings provided herein. For example, benzothiazole derivatives listed herein with reference numerals 143-202 and 204-229 can be prepared according to procedures analogous to those described herein for related compounds.
EXAMPLE 203 [(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl-aminoj-acetic acid The title compound was prepared according to the procedures for EXAMPLE 20 and EXAMPLE 18 using sarcosine ethyl ester hydrochloride. MS (ESI): mass calculated for C24H27N3O5S, 469.56; m/z found, 470.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J= 8.02, 1H), 7.65 (d, J= 8.02, 1H), 7.34-7.40 (m, 1H), 7.23-7.30 (m, 3H), 6.92-6.98 (m, 2H), 4.34-4.44 (m, 2H), 3.92 (brs, 2H), 3.45-3.54 (m, 3H), 3.35 (brs, 1H), 3.25 (brs, 1H), 3.12 (s, 2H), 2.96 (s, 1H), 2.76 (brs, 2H), 1.92-2.08 (m, 4H).
EXAMPLES 230-231 and 485 / As indicated in the context of this written description, compounds of this invention that are referred to herein for which no explicit preparation description is provided can be prepared according to procedures analogous to those described herein in light of the knowledge of one of ordinary skill in the art and the teachings provided herein. For example, benzoimidazole derivatives listed herein with reference numerals 230-231 and 485 can be prepared according to procedures analogous to those described herein for related compounds. o 156 544938 EXAMPLE 250 0 1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid.
A. 1-(4-Benzyloxv-benzvl)-piperidine-4-carboxylic acid ethvl ester. A mixture of 4-benzyloxybenzyi chloride (15.2 g, 65.3 mmol), isonipecotic acid ethyl ester (15 mL, 97 mmol), and K2CO3 (13.5 g, 97.6 mmol) in CH3CN (300 mL) was stirred at reflux for 20 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure to yield a clear 10 golden oil. This material was diluted with /PrOH (100 mL), and the mixture was filtered. The solid was air dried to yield a white solid (19.7 g, 85% yield). TLC (Si02, 15% acetone/CH2Ci2): Rf = 0.32. MS (ESI): mass calculated for C22H27N03, 353.2; m/z found, 354.3 [M+Hf. 1H NMR (400 MHz, DMSO-ofe): 7.44 (d, J = 7.1, 2H), 7.39 (t, J = 7.1, 2H), 7.33 (d, J = 7.2, 1H), 7.18 (d, J = 8.2, 15 2H), 6.94 (2H, J = 8.6, 2H), 5.08 (s, 2H), 4.04 (q, J = 7.09, 2H), 2.72 (d, J = 11.5, 2H), 2.32-2.18 (m, 1H), 1.94 (t, J = 11.6, 2H), 1.76 (d, J = 10.2, 2H), 1.59-1.48 (m, 2H), 1.17 (t, J = 7.1, 3H).
B. 1-(4-Hvdroxv-benzvn-piperidine-4-carboxvlic acid ethvl ester. 1-(4-Benzyloxy-benzyi)-piperidine-4-carboxylic acid ethyl ester (10.0 g, 28.3 /nmoi) 20 was dissolved in 1:1 ethanol/ethyl acetate (150 mL). To this solution was added Pd on carbon (10 wt %, 503 mg) as a suspension in ethanol (5.0 mL). The resulting suspension was placed on a Parr hydrogenator at 40 psi of H2 and shaken overnight. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure 25 to give a clear golden oil. The oil was purified on Si02 (90 g; 50% acetone/CH2Cl2) to give a white solid (2.0 g, 27% yield). TLC (Si02, 50% acetone/CH2Cl2): Rf = 0,32. MS (ESI): mass calculated for C15H21NO3, 263.2; m/z found, 264.2 [M+Hf. 1H NMR (400 MHz, DMSO-ofe): 9.25 (s, 1H), 7.05 (d, J = 8.4, 2H), 6.68 (d, J = 8.4, 2H), 4.04 (q, J = 7.1, 2H), 3.34 (s, 2H), 2.71 (d, J 157 544938 = 11.5, 2H), 2.32-2.18 (m, 1H), 1.92 (t, J= 11.6, 2H), 1.76 (d, J=10.2, 2H), 1.59- 1.48 (m, 2H), 1.17 (t, J = 7.1, 3H).
C, 144-(Ben2othiazol-2-vloxvVbenzvll-piperidine-4-carboxvlic acid ethvl ester. To a stirring solution of 1-(4-hydroxy-benzyl)-piperidine-4-carboxylic acid ethyl ester (508 mg, 1.93 mmol) in CH3CN (15 mL), was added K2CO3 (564 mg, 4.1 mmol) and 2-chlorobenzothiazole (0.50 mL, 4.0 mmol). The suspension was heated to 80 °C and stirred overnight. The reaction mixture was allowed to cool to room temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified 10 on Si02 (12 g; 0-15% acetone/CH2CI2) to give a clear and colorless tacky oil (717 mg, 94% yield). TLC (SiOz, 15% acetone/CH2CI2): Rf = 0.5. MS (ESI): mass calculated for C22H24N203S, 396.2; m/z found, 397.3 [M+Hf. 1H NMR (400 MHz, DMSO-de): 7.92 (d, J = 8.0, 1H), 7.68 (d, J = 8.0, 1H), 7.48-7.33 (m, 5H), 7.33 (t, J = 7.1, 1H), 4.06 (q, J = 7.1, 2H), 3.49 (s, 2H), 2.76 (d, J = 11.5, 15 2H), 2.34-2.22 (m, 1H), 2.02 (t, J= 11.6, 2H), 1.80 (d, J= 10.2, 2H), 1.64-1.54 (m, 2H), 1.18 (t, J = 7.1, 3H).
D. 1 -f4-(Benzothiazol-2-vloxv)-benzvn-piperidine-4-carboxviic acid. To a stirring solution of 1-[4-(benzothiazol-2-yloxy)-benzyi]-piperidine-4-carboxylic acid ethyl ester (663 mg, 1.7 mmol) in 25% /Pr0H/H20 (20 mL) was added potassium hydroxide (206 mg, 3.1 mmol). The reaction mixture was stirred at room temperature for 20 h, and the solution was treated to pH 5.5 with J M HCI. The resulting solution was extracted with 10% /PrOH/CHCIs (3 x 50 mL). The combined extracts were dried (MgSC^), filtered, and concentrated under reduced pressure to yield a white solid (561 mg, 91% yield). MS (ESI): mass 25 calculated for C2oH2oN203S, 368.1; m/z found, 369.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 7.92 (d, J= 7.6, 1H), 7.69 (d, J = 7.6, 1H), 7.48-7.34 (m, 5H), 7.33 (t, J = 7.1, 1H), 3.49 (s, 2H), 2.76 (d, J = 11.4, 2H), 2.22-2.11 (m, 1H), 2.02 (t, J=11.2, 2H), 1.80 (d, J= 13.2, 2H), 1.62-1.48 (m, 2H), 1.18 (t, J ~ 7.1, 3H).
EXAMPLE 251 158 544938 1-{1-[4-(Benzothiazol-2-y!oxy)-benzyl]-piperidin-4-yi}-pyrrolidin-2-one.
A. 4-fBenzothiazoi-2-vloxv)-benzaldehvde. To a mixture of 4- hydroxybenzaldehyde (1 g, 8.2 mmol) and 2-chlorobenzothiazoie (2.03 mL, 16.4 mmol) in CH3CN (100 mL) was added Cs2C03 (5.5 g, 17,2 mmol). The reaction mixture was stirred at 60 °C for 24 h. The resulting mixture was cooled to room temperature, filtered through diatomaceous earth and concentrated under reduced pressure to yield the crude product as an orange 10 oil. The oil was triturated with hexanes/CH2CI2 (100 mL) and the solvent layer decanted and concentrated under reduced pressure to yield an orange oil which was further purified on Si02 (120 g; 0-50% ethyl acetate/hexanes) to give a white solid (853 mg, 41% yield). 1H NMR (400 MHz, CDCI3): 10.1 (s, 1H), 7.97-7.78 (m, 2H), 7.78-7.70 (m, 2H), 7.60-7.50 (m, 2H), 7.48-7.38 (m, 15 1H), 7.36-7.30 (m, 1H).
B. 1-f1-f4-(Benzothiazol-2-vloxvVbenzvn-piperid!n~4-vn-pvrroiidin-2-one. A mixture of 4-(benzothiazol-2-yioxy)-benzaldehyde (500 mg, 1.9 mmol), 1-piperidin-4-yi-pyrrolidin-2-one hydrochloride (440 mg, 2.2 mmoi), Et3N (300 |j,L, 2.2 mmol) and molecular sieves (500 mg, crushed, 4A) in CICH2CH2CI (/10 mL) was stirred at room temperature for 1 h. To the resulting mixture was added NaBH(OAc)3 (830 mg, 3.92 mmol). The mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth, rinsed with CH2CI2 (50 mL) and concentrated under reduced pressure to yield the crude product , as a yellow oil. The crude product was purified on Si02 (40 g; 0-100% 25 acetone/CH2C!2) to give a clear oil which crystallized on standing (287 mg, 36% yield). MS (ESI): mass calculated for C23H25N302S, 407.5; m/z found, 408.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.76 (d, J = 8.0, 1H), 7.69 (d, J = 8.0, 1H), 7.41-7.30 (m, 3H), 7.35-7.27 (m, 3H), 4.46-3.98 (m, 1H), 3.71 (s, 2H), 3.36 (t, J = 6.9, 2H), 2.97 (d, J = 11.7, 2H), 2.40 (t, J = 8.1, 2H), 2.17-1.97 (m, 4H), 30 1.81-1.62 (m, 4H). 159 544938 EXAMPLE 252 F 2~(2-Fluoro-4-piperidin-1-ylmethyl-phenoxy)-benzothiazole.
A. (3-Fluoro-4-hvdroxy-phenv))-piperidin-1-yl-methanone. A solution of 3-fiuoro-4-hydroxybenzoic acid (5.0 g, 32 mmol), piperidine (5 mL, 51 mmol), and EDCI (9.3 g, 49 mmol) in CH2CI2 (100 mL) was stirred at room temperature for 20 h. The reaction mixture was added to CH2CI2 (200 mL) and was washed with 1 M HCI (2 x 100 mL). The organic layers were combined, dried (MgS04), 10 and concentrated under reduced pressure to yield a clear golden oil. The oil was purified on Si02 (120 g; 0-10% acetone/CH2CI2) to give a white solid (2.4 g, 34% yield). TLC (Si02, 15% acetone/CH2CI2): Rf = 0.35. MS (ESi): mass calculated for C12H14FN02l 223.1; m/z found, 224.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 10.26 (s, 1H), 7,18 (d, J = 11.6, 1H), 7.00 (d, J = 8.3, 1H), 15 6.98 (t, J = 8.5, 1H), 3.42 (br s, 4H), 1.65-1.45 (m, 6H).
B. 2-Fluoro-4-pjperidin-1 -vlmethvl-phenoi, A solution of lithium aluminum hydride (1.9 g, 50 mmo!) in THF (40 mL) was stirred at 5 °C. To the mixture was added (3-ffuoro-4-hydroxy-phenyi)-piperidin-1-yi-methanone (2.3 g, 10.4 mmol) in THF (10 mL) over 15 min and then the mixture was heated to ^0 °C.
After 20 h the mixture was cooled to 5 °C and saturated NH4CI (200 mL) was added followed by CH2CI2 (200 mL). The organic layer was separated, dried (MgS04), and concentrated under reduced pressure to yield a white solid (812 mg, 37% yield). TLC (Si02, acetone): Rf=0,22, MS (ESI): mass calcuiated forC12H16FNO, 209.1; m/z found, 210.3 [M+Hf. 1H NMR (400 MHz, DMSO-25 cfe): 6.58 (d, J = 13.4, 1H), 6.48 (d, J = 8.2, 1H), 6.40 (t, J = 9.9, 1H), 3.14 (s, 2H), 2.24 (br s, 4H), 1.54-1.30 (m, 6H).
C. 2-(2-Fluon>4-piperidin-1 -ylmethvl-phenoxvVbenzothiazole. To a stirring solution of 2-fiuoro-4-piperidin-1-ylmethyl-phenol (152 mg, 0.73 mmol) in CH3CN (10 mL), was added K2CO3 (201 mg, 1.5 mmol) and 2- chlorobenzothiazole (0.14 mL, 1.1 mmol). The suspension was heated to 80 °C and stirred overnight. The reaction mixture was allowed to cool to room 160 544938 temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified on Si02 (12 g; 0-50% acetone/CH2C!2) to give a clear golden oil (142 mg, 57% yield). TLC (Si02, 50% acetone/CH2CI2): Rf = 0.44. MS (ESI): mass calculated for 5 C19Hi9FN2OS, 342.1; m/z found, 343.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 7.95 (d, J = 7.9, 1H), 7.69 (d, J = 7.5, 1H), 7.56 (t, J = 8.2, 1H), 7.47-7.32 (m, 3H), 7.44 (d, J= 15.4, 1H), 3.48 (s, 2H), 2.36 (s, 4H), 1.63-1.37 (m, 6H).
EXAMPLE 253 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-2-hydroxy-acetamide.
A. f1-f4-(Benzothiazol-2-vloxv)-benzvH-piperidin-4-vl>-carbamic acid tert-butvl 15 ester. A mixture of 4-(benzothiazol-2~yloxy)-benzaidehyde (EXAMPLE 251, step A, 500 mg, 1.9 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (785 mg, 3.9 mmol) and molecular sieves (500 mg, crushed, 4A) in CICH2CH2CI (10 mL) was stirred at room temperature for 40 min. To the resulting reaction mixture was added NaBH(OAc)3 portion wise over 1.5 h (4 x 207 mg, 3.^ 20 mmol). The resulting mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth and rinsed with CH2CI2 (50 mL). The filtrate was washed with sat. aq. NaHCOs (1 x 25 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a light yellow oil. The crude product was purified on Si02 (40 g; 0-5% 2 M NH3 in CH3OH/CH2CI2) to 25 give a white foam (504 mg, 59% yield). MS (ESI): mass calculated for C24H29N3O3S, 439.6; m/z found, 440.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.67 (d, J = 8.0, 1H), 7.42-7.36 (m, 3H), 7.32-7.24 (m, 3H), 4.44 (brs, 1H), 3.50 (s, 2H), 2.82-2.76 (m, 2H), 2.16-2.06 (m, 2H), 1.96-1.88 (m, 2H), 1.45 (s, 9H), 1.48-1.38 (m, 2H).
H 161 544938 B. 1-f4-(Benzothiazol-2-vloxv)-benzvn-piperidin-4~vlamine. To a solution of {1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (200 mg, 0.45 mmo!) in CH2CI2 (2 mL) at 0 °C was added 4 N HCI in dioxane (1.8 mL, 7.2 mmol) dropwise. The resulting reaction mixture was stirred at 5 room temperature for 2 h. The desired product was isolated by filtration and was rinsed with Et20 (50 mL) to yield a white powder (187 mg, 100% yield). MS (ESI): mass calculated for C19H21N3OS, 339.5; m/z found, 340.4 [M+H]+, 1H NMR (400 MHz, CDCI3): 7.68-7.64 (m, 1H), 7.58-7.52 (m, 2H), 7.48-7.44 (m, 1H), 7.40-7.35 (m, 2H), 7.30-7.24 (m, 1H), 7.20-7.14 (m, 1H), 4.25 (s, 2H), 10 3.52-3.46 (m, 2H), 3.36-3.28 (m, 1H), 3.08-2.99 (m, 2H), 2.16-2.08 (m, 2H), 1.92-1.80 (m, 2H).
C. Acetic acid (1-r4-fbenzothiazol-2-vloxv)-benzvll-piperidin-4-vlcarbamovl'i-methvl ester. To a solution of {1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylamine dihydrochloride (413 mg, 1.0 mmol) in CH2CI2 (20 mL) at room temperature was added TEA (0.70 mL, 5.0 mmol), followed by acetoxyacetyl chloride (0.16 mL, 1.5 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was dissolved in CH2CI2 (100 mL), washed with sat. aq. NaHC03 (1 x 25 ml), dried (Na2SC>4) and concentrated under reduced pressure to yield the crude product as an off-white 20 solid. The crude product was purified on SiC>2 (40 g; 0-10% CH3OH/CH2CI2) to give a white solid (410 mg, 93% yield). MS (ESi): mass calculated for C23H25N3O4S, 439.2; m/z found, 440.4 [M+H]+. 1H NMR (400 MHz, CDC!3): 7,72 (d, J = 7.8, 1H), 7.65 (d, J = 8.1, 1H), 7.40-7.35 (m, 3H), 7.32-7.23 (m, 3H), 6.11 (d, J = 8.3, 1H), 4.53, (s, 2H), 3.93-3.82 (m, 1H), 3.50 (s, 2H), 2.83 25 (d, J- 11.9, 2H), 2.15 (s, 3H), 2.14 (t, J= 11.9, 2H), 1.93 (d, J= 12.1, 2H), 1.56-1.45 (m, 2H).
D. N-(1-r4-fBenzothiazol-2-vloxv)-benzvn-piperidin-4-vl)-2-hvdroxv-acetamide. To a solution of acetic acid {1-[4-(benzothiazo!-2-yloxy)-benzyi]-piperidin-4-ylcarbamoylj-methyl ester (368 mg, 0,84 mmol) in THF (30 mL), CH3OH (10 mL) and H2O (10 mL) was added lithium hydroxide (80.2 mg, 3.34 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was extracted with CH2CI2 (30 mL x 3). The combined organic phases were concentrated under reduced pressure to yield the crude product as an off-white 162 544938 solid. The crude product was purified on S1O2 (40 g; 0-10% CH3OH/CH2CS2) to give a white solid (297 mg, 82% yield). MS (ESI): mass calculated for C21H23N3O3S, 397.2; m/z found, 398.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 7.8, 1H), 7.65 (d, J = 8.1, 1H), 7.40-7.35 (m, 3H), 7.31-7.23 (m, 5 3H), 6.83 (d, J = 8.1, 1H), 5.33 (br s, 1H), 3.99 (s, 2H), 3.87-3.75 (m, 1H), 3.50 (s, 2H), 2.85 (d, J = 11.4, 2H), 2.14 (t, J = 10.9, 2H), 1.92 (d, J = 12.6, 2H), 1.56-1.43 (m, 2H).
EXAMPLE 254 1-(2-{[4-(Benzothiazol-2-yloxy)~benzyl]-cyclopropyl-amino}-ethyl)-4-hydroxy-pyrrolidin-2-one.
A, r4-(Benzothiazol-2-vloxv)-benzvn-cvclopropvl-amine. A mixture of 4-15 (benzothiazol-2-yloxy)-benzaldehyde (5.0 g, 19.6 mmoi), cyciopropylamine (3.35 g, 58.7 mmol) in CICH2CH2CI (80 mL) was stirred at room temperature for 40 min. To the resulting reaction mixture was added NaBH(OAc)3 portion wise over 1.5 h (4 x 2.1 g, 39.2 mmol). The resulting mixture was stirre^ at room temperature for 24 h, filtered through diatomaceous earth and rinsed with 20 CH2CI2 (500 mL). The filtrate was washed with sat. aq. NaHC03 (1 x 250 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a pale yellow oil. The crude product was purified on S1O2 (330 g; 0-5% CH3OH/CH2CI2) to give a white solid (3.95 g, 68% yield). MS (ESI): mass calculated for Ci7H16N2OS, 296.1; m/z found, 297.3 [M+Hf. 1H NMR (400 25 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.40-7.33 (m, 3H), 7.32-7.27 (m, 2H), 7.24 (t, J = 8.1, 1H), 3.85 (s, 2H), 2.19-2.12 (m, 1H), 1.86 (brs, 1H), 0.48-0.35 (m, 4H).
B. f2-M-fBenzothiazol-2-vloxv1-benzvl1-cvclopropvl-amino)-ethvD-carbamic acid tert-butvl ester. To a solution of [4-(benzothiazol-2-ytoxy)-benzyi]- cyclopropyl-amine (2.96 g, 10 mmol) in CH3CN (40 mL) at room temperature 163 544938 was added /\/,A/-diisopropylethylamine (3.48 ml, 20 mmoi), followed by (2-bromo-ethyi)-carbamic acid tert-butyl ester (3.36 g, 15 mmol). The resulting mixture was heated at 60 °C overnight. The mixture was cooled and dissolved in CH2CI2 (200 mL), washed with sat. aq. NaHCOs (1 x 25 mL) and H20 (2 x 25 5 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a pale yellow solid. The crude product was purified on Si02 (120 g; 0-50% ethyl acetate/hexanes) to give a white solid (3.44 g, 78% yield). MS (ESI): mass calculated for C^HagNaOsS, 439.2; m/z found, 440.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.64 (d, J = 8.1, 1H), 7.39-10 7.22 (m, 6H), 4.75 (br s, 1H), 3.74 (s, 2H), 3.25 (dd, J = 5.8, 6.1, 2H), 2,65 (t, J = 6.3, 2H), 1.82-1.75 (m, 1H), 1.43 (s, 9H), 0.54-0.48 (m, 2H), 0.43-0.37 (m, 2H), C. N1-f4-fBenzothiazol-2-vloxvVbenzvl1-N1-cvclopropyl-ethane-1,2-diamine. To a solution of (2-{[4-(benzothiazol-2-yIoxy)-benzyl]-cyclopropyl-amino}-ethyl)-15 carbamic acid tert-butyl ester in CH2CI2 (16 mL) at 0 °C was added trifluoroacetic acid in dioxane (4 mL) dropwise. The resulting reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to yield the crude product as a pale yellow oil. The oil was dissolved in CH2Cl2 (100 mL), washed with sat. aq. NaHC03 (1 x 25 mL), dried (Na2S04) 20 and concentrated under reduced pressure to yield the product as a clear oil. MS (ESI): mass calculated for C19H21N3OS, 339.1; m/z found, 340.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, 8,1, 1H), 7.61 (d, J= 8.1, 1H), 7.37-7.18 (m, 6H), 3.75 (s, 2H), 2.76 (t, J = 6.3, 2H), 2.60 (t, J = 6.3, 2H), 1.98 (s, 2H), 1.79-1.73 (m, 1H), 0.51-0.45 (m, 2H), 0.42-0.37 (m, 2H). 25 D. 1-f2-ff4-fBenzothiazol-2-vloxv)-benzvll-cvciopropyl-amino>-ethvlV4-hvdroxv-pvrrolidin-2-one, To a solution of N1-[4-(benzothiazol-2-yloxy)-benzyl]-N1-cyclopropyl-ethane-1,2-diamine (1.5 g, 4.4 mmol) in CH3CN (18 mL) at room temperature was added A/,A/-diisopropyIethylamine (1.15 mL, 6.63 mmoi), followed by 4-(R)~bromo-3-hydroxy-butyric acid ethyl ester (1.11 g, 5,3 mmol). 30 The resulting mixture was heated at 60 °C overnight. The mixture was cooled and dissolved in CH2CI2 (100 mL), washed with sat. aq. NaHCOs (1x10 mL) and H20 (2x10 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a light brown oil. The crude product was 544938 purified on reverse phase HPLC (0-99%, 0.05 % TFA in H20/CH3CN) to give a clear oil (435 mg, 18.3% yield). MS (ESi): mass calculated for C23H25N3O3S, 423.2; m/z found, 424.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.64 (d, J= 8.1, 1H), 7.58-7.54 (m, 2H), 7.49 (d, J = 8.1, 1H), 7.37-7.33 (m, 2H), 7.26 (t, J = 7.6, 5 1H), 7.16 (t, J = 7.6, 1H), 4.48 (dd, J = 8.8, 12.9, 2H), 4.32 (t, J = 5.8, 1H), 3.84-3.75 (m, 1H), 3.64-3.56 (m, 2H), 3.38 (t, J = 6.3, 2H), 3.24 (t, J = 10.9, 1H), 2.73-2.66 (m, 1H), 2.59 (dd, J = 6.3, 11.1, 1H), 2.15 (d, J= 17.2, 1H), 0.79 (d, J = 6.6, 4H).
EXAMPLE 255 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-y!}-N-methyI-methanesulfonamide.
A. {1-l4-(Benzothiazol-2-vloxv)-benzvll-DiDeridin-4-vl}-methvl-carbamic acid tert-butvl ester. A mixture of 4-(benzothiazol-2-yloxy)-benzaldehyde (4.4 g, 17.2 mmol), methyl-piperidin-4-yi-carbamic acid tert-butyl ester (4.06 g, 18.9 mmol) in CICH2CH2CI (172 mL) was stirred at room temperature for 40 min. To the resulting reaction mixture was added NaBH(OAc)3 portion wise ove/1.5 h 20 (4x 1.82 g, 34.4 mmol). The resulting mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth and rinsed with CH2CI2 (300 mL). The filtrate was washed with sat. aq. NaHC03 (1 x 50 mL), dried (Na2SC>4) and concentrated under reduced pressure to yield the crude product as a paie yellow oil. The crude product was purified on Si02 (330 g; 0-100% ethyl 25 acetate/hexanes) to give a light yellow foam (3.75 g, 48% yield). MS (ESI); mass calculated for C25H31N3O3S, 453.2; m/z found, 454.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J= 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7.41-7.35 (m, 3H), 7.33-7.23 (m, 3H), 4.13-3.94 (m, 1H), 3.53 (s, 2H), 2.93 (d, J = 11.6, 2H), 2.74 (s, 3H), 2.08 (t, J = 11.6, 2H), 1.81-1.69 (m, 2H), 1.65-1,57 (m, 2H), 1.46 30 (s, 9H). 165 WO 2005/012297 PCT/US2004/024309 B. (1-f4-fBen2othiazol-2-vloxv)-benzyll-piperidin-4-vl}-methvl-amine. To a solution of {1 -[4-(benzothiazol-2-yloxy)-benzyi]-piperidin-4-yi}-methy!-carbamic acid tert-butyl ester (3,7 g, 8,2 mmol) in CH2Cl2 (41 mL) at 0 °C was added 4 N HCI in dioxane (8.2 mL, 32.6 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The desired product was isolated by filtration and was washed with Et20 (150 mL) to yield a white powder (3,38 g, 97% yield). MS (ESI): mass calculated for C2oH23N3OS, 353.2; m/z found, 354.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 8.92 (br s, 1H), 7.72 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.39-7.33 (m, 3H), 7.30-7.21 (m, 3H), 3.49 (s, 2H), 10 2.98-2.86 (m, 3H), 2,63 (s, 3H), 2.08-1.98 (m, 4H), 1.84-1.71 (m, 2H).
C. N41-r4-(rBenzothiazol-2-vloxvVbenzy[]-piperidin-4-yll-N-methvl-methanesulfonamide. To a solution of (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methyl-amine dihydrochloride (354 mg, 1,0 mmol) in CH2CI2 (20 mL) at room temperature was added TEA (0.70 mLt 5.0 mmol), followed by methanesulfonyl chloride (0.12 mL, 1.5 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was dissolved in CH2CI2 (100 mL), washed with sat. aq. NaHC03 (1 x 25 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a pale yellow solid. The crude product was purified on Si02 (40 g; 0-10% CH30H/CH2CI2) to give a white solid (378 mg, 88% yield). MS (ESI): mass calculated for C21H25N303S2, 431.1; m/z found, 432,4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7.41-7.35 (m, 3H), 7.33-7.23 (m, 3H), 3.80-3.70 (m, 1H), 3.50 (s, 2H), 2.96 (d, J= 11.6, 2H), 2.82 (s, 3H), 2.80 (s, 3H), 2.08 (t, J = 11.6, 2H), 1.89-1.77 (m, 2H), 1.70-1.60 (m, 2H).
EXAMPLE 256 ctuXCV.
HN-n 2-{4-[4-(1H-Tetrazol-5-yl)-piperidin-1-ylmethyl]-phenoxy}-benzothiazo!e. 166 544938 A solution of 4-(benzothiazol-2-yloxy)-benzaldehyde (EXAMPLE 251 step A, 620 mg, 2.4 mmol), 4-(1H-tetrazol-5-yl)-piperidine hydrochloride (565 mg, 3.0 mmol), and Et3N (0.43 mL, 3.1 mmol) in 30% THF/CH2CI2 (35 mL) was stirred 5 at room temperature for 30 min. To the stirring mixture was added NafAcCOsBH (787 mg, 3.7 mmol). After 20 h the reaction mixture was added to 10% /PrOH/HaO (50 mL) and the organic layer was separated and dried (MgS04). The solvent was removed under reduced pressure to yield a clear yellow tacky oil. This material was diluted with ethanol (10 mL), heated to 80 10 °C, and filtered while hot. To the filtrate was added Et20 (10 mL) and the flask was cooled on ice. A solid formed and was filtered to yield a white solid (48 mg, 5% yield). MS (ESI): mass calculated for C20H20N6OS, 392.1; m/z found, 393.4 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.95 (d, J= 7.9, 1H), 7.70 (d, J = 7.9, 1H), 7.53-7.35 (m, 5H), 7.33 (t, J- 7.9, 1H), 3.59 (s, 2H), 3.09-3.00 (m, 15 1H), 2.91 (d, J= 10.8, 2H), 2.22 (t, J = 9.8, 2H), 1.85-1.72 (m, 2H).
EXAMPLE 257 1-{4-[4-(Benzothiazoi-2-yloxy)-benzyl]-piperazin-1-yl}-2-hydroxy-ethanone.
A. 4-f4-(Benzothiazol-2-vioxy)-benzvn-piperazjne-1-carboxylic acid tert-butyl ester. A mixture of 4-(benzothiazol-2-yloxy)-benzaldehyde (2.5 g, 9.8 mmol), piperazine-1-carboxylic acid tert-butyl ester-2-one (3.7 g, 19.6 mmol) and molecular sieves (2.5 g, crushed, 4A) in CICH2CH2CI (25 mL) was stirred at 25 room temperature for 40 min. To the resulting reaction mixture was added NaBH(OAc)3 portion wise over 1.5 h (4 x 504 mg, 19.6 mmol). The resulting mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth and rinsed with CH2Cl2 (200 mL). The filtrate was washed with sat. aq. NaHC03 (1 x 50 mL), dried (Na2S04) and concentrated under 30 reduced pressure to yield the crude product as a yellow semi-solid. The crude o I 167 544938 product was purified on SiC>2 (120 g; 0-100% acetone/CH2C!2) to give an off-white solid (1.72 g, 42% yield). MS (ESI): mass calculated for C23H27N3O3S, 425.5; m/z found, 426.4 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.74 (d, J = 8.2, 1H), 7.67 (d, J = 8.2, 1H), 7.42-7.37 (m, 3H), 7.4-7.25 (m, 3H), 3.53 (s, 2H), 5 3.45 (br t, J = 4.9, 4H), 2.41 (br t, J = 4.5, 4H), 1.46 (s, 9H).
B. 2-f4-Fiperazin-1 -vlmethvl-phenoxv)-benzothiazole. To a solution of 4-[4-(benzothiazoi-2-yloxy)-benzylj-piperazine-1-carboxyIic acid tert-butyl ester (1.7 g, 4.0 mmol) in CH2Ci2 (20 mL) at 0 °C was added 4 N HCI in dioxane (5 mL, 20 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to yield the crude product as a white solid. The crude product was triturated with Et20 (50 mL) and isolated by filtration to yield the desired product as a white powder (1.37 g, 87% yield). MS (ESI): mass calculated for C18H19N3OS, 325.4; m/z found, 326.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.81 (d, J~ 8.0, 1H), 7.77-7.72 (m, 2H), 7.62 (d, J = 15 8.2, 1H), 7.57-7.53 (m, 2H), 7.45-7.40 (m, 1H), 7.35-7.31 (m, 1H), 4.45 (s, 2H), 3.62 (brs, 8H).
C. 1-(4-[4-fBenzothiazol-2-vioxvVbenzvl1-piperazin-1-vlV2-hvdroxv-ethanone. To a mixture of glycolic acid (47 mg, 0.62 mmol) and HOBT (1.25 mL, 0.62 mmol, 0.5 M in DMF) in CH2CI2 (25 mL) was added 2-(4-piperazin-1-yimethyi- phenoxy)-benzothiazole (150 mg, 0.42 mmol) followed by EDCI (150 mg, 0.79 mmol). The resulting mixture was stirred at room temperature for 24 h, fluted with CH2Cf2 (50 mL) and washed with sat. aq. NaHCCh (1 x 20 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure to yield the crude product as apale yellow oil. The crude product was purified on 25 Si02 (40 g; 0-3% 2 M NH3 in CH3OH/CH2Ci2) to give a white foam (93 mg, 59% yield). MS (ESI): mass calculated for C20H21N3O3S, 383.5; m/z found, 384.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.68 (d, J = 8.0, 1H), 7.45-7.25 (m, 6H), 4.16 (d, J = 4.1, 2H), 3.71-3.68 (m, 2H), 3.64-3.61 (m, 1H), 3.55 (s, 2H), 3.32-3.25 (m, 2H), 2.53-2.44 (m, 4H). 168 544938 EXAMPLE 258 N-{1-[4-(Benzothiazol-2-yloxy)-benzy!]-piperid!n-4-yimethyl}-rriethanesulfonamide.
A. (1-[4-fBenzothiazol-2-vloxyVbenzvn-piperidin-4-vlmethvl)-carbamic acid tert-butyl ester. A mixture of 4-(benzothiazol-2-yioxy)-benza!dehyde (1.0 g, 3.9 mmol), piperidin-4-ylmethyl-carbamic acid tert-butyl ester (1.3 g, 5.9 mmol) and molecular sieves (1.0 g, crushed, 4A) in CICH2CH2CI (15 mL) was stirred at room temperature for 40 min. To the resulting mixture was added NaBH(OAc)3 portion wise over 1.5 h (4 x 412 mg, 7.8 mmol). The mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth and rinsed with CH2CI2 (100 mL). The filtrate was washed with sat. aq. NaHCOg (1 x 50 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude 15 product as a yellow semi-solid. The crude product was purified on Si02 (40 g; 0-100% acetone/CH2CI2) to give a white foam (890 mg, 50% yield). MS (ESi): mass calculated for C25H31N3O3S, 453.6; m/z found, 454.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.67 (d, J= 8.0, 1H), 7.41-7.36 (m, 3H), 7.32-7.24 (m, 3H), 4.59 (br s, 1 H), 3.50 (s, 2H), 3.06-3.00 (m, 2H)/2.94-20 2.88 (m, 2H), 1.97 (t, J = 11.4, 2H), 1.68 (d, J = 11.4, 2H), 1.44 (s, 9H), 1.22-1.33 (m, 2H).
B. C-(1-r4-fBenzothiazol-2-vloxvVbenzvn-piperidin-4-vlVmethvlamine. To a solution of {1 ~[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamic acid tert-butyl ester (866 mg, 1.9 mmol) in CH2CI2 (5 mL) at 0 °C was added 4 N HCI in dioxane (2.4 mL, 9.5 mmol) dropwise. The resulting mixture was stirred at room temperature for 24 h and concentrated under reduced pressure to yield the crude product as a white solid. The crude product was triturated with Et20 (50 mL) and isolated by filtration to yield the desired product as a white powder (813 mg, 100% yield). MS (ESI): mass calculated for 30 C20H23N3OS, 353.5; m/z found, 354.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 169 544938 7.80 (d, J = 8.0, 1H), 7.69 (d, J = 8.6, 2H), 7.60 C. N-{1-[4-(Benzothiazol-2-vloxv)-benzvn-piperidin-4-vlmethviy- methanesulfonamide. To a mixture of C-{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methylamine (150 mg, 0.39 mmoi) in CH2CI2 (5 mL) was added Et3N (400 jlxL, 2.86 mmol). The resulting mixture was cooled to 0 °C and CH3SO2CI was added via syringe (41 |xL, 0.52 mmoi). The mixture was stirred 10 at room temperature for 24 h, diluted with CH2CI2 (10 mL) and washed with sat. aq. NaHCOs (1x5 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a white solid. The crude product was purified on Si02 (10 g; 0-3% 2 M NH3 in CH3OH/CH2Ci2) to give a white solid (112 mg, 67% yield). MS (ESI): mass 15 calculated for C2iH25N303S2, 431.6; m/z found, 432.4 [M+H]+, 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.67 (d, J = 8.0, 1H), 7.42-7.36 (m, 3H), 7.33-7.25 (m, 3H), 4.25 (br t,J~ 6.6, 1H), 3.51 (s, 2H), 3.04 (d, J = 6.6, 2H), 2.96 (s, 3H), 2.91-2.84 (m, 2H), 1.98 (t, J = 11.7, 2H), 1.74 (br d, J = 12.7, 2H), 1.60-1.48 (m, 2H), 1.36-1.24 (m, 2H). 3-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxazolidin-2-one.
A. 3-Piperidin-4-vl-oxazolidin-2-one hydrochloride salt. To a solution of 1-benzyl-4-piperidinone (10.3 g, 54 mmol) and ethanolamine (13.2 mL, 218 mmol) in CH3OH (20 mL) was added sodium cyanoborohydride (10.2 g, 163 mmol) and trifluoromethanesulfonic acid (5 mL) and the reaction was stirred at 23 °C for 3 days. The mixture was cooled to 0 °C and 12 N HCI was slowly 30 added until gas evolution ceased and the resulting mixture was stirred for a EXAMPLE 259 170 544938 further 3 h. The mixture was filtered and the filtrate concentrated under reduced pressure. The crude oil was redissolved in H2O {50 mL), the solution was made basic by the addition of 10 N NaOH. The mixture was extracted with CH2CI2 (8 x 70 mL). The combined CH2Cl2 extracts were dried and 5 concentrated under reduced pressure to yield the crude product (12.0 g, 95%). A solution of 2-(1-benzyl-piperidin-4-ylamino)-ethanol (3.6 g, 15.3 mmol) in CICH2CH2CI (5 mL) was treated with carbonyl diimidazole (CDI) (2.6 g, 16 mmol) and the mixture stirred at 23 °C for 30 min. The mixture was diluted with CH2CI2 (100 mL), washed with H2O (1 x 50 mL) and sat. aq. NaHCOs (1 x 50 10 mL), dried, and concentrated under reduced pressure to yield 2.85 g (65%) of 3-(1-benzyi-piperidin-4-yl)-oxazolidin-2-one. To a solution of 3-(1-benzyl-piperidin-4-yl)-oxazoIidin-2-one (2.3 g, 8.8 mmol) in CICH2CH2CI (40 mL) was added a-chloroethyl acetylchloride (1.5 g, 10.6 mmol) and the mixture was heated to 100 °C for 90 min. The mixture was cooled to 23 °C and 15 concentrated under reduced pressure. The crude residue was dissolved in CH3OH and heated to reflux for 1 h. The mixture was cooled to 0 °C and concentrated under reduced pressure to yield the title compound (1.89 g, 99%). MS (ESI): exact mass calculated for 170,1; m/z found, 171.2 [M+Hf. 1H NMR (400 MHz, DMSO-de): 8.97 (brs, 2H), 4.27 (dd, J = 20 9.1, 7.8, 2H), 3.80 (tt, J = 11.8, 4.2, 1H), 3.49 (dd, J = 8.0, 6.6, 1H), 3.30 (br d, J = 12.7, 2H), 2.97 (dt, J = 12.6, 2.3, 2H), 1.90 (ddd, J = 16.6, 13.0, 4.1 y2H), 1.86-1.75 (m, 2H).
B. f4-fBenzothiazol-2-vioxv)-phenvn-methanol. To a mixture of 4-hydroxybenzyl alcohol (12 g, 97 mmol) in CH3CN (200 mL) containing K2C03 25 (22 g, 159 mmo!) was added 2-chforobenzothiazole (22 g, 130 mmol) and the mixture was heated to reflux for 72 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give the crude product as a golden oil. The crude oil was purified on Si02 (300 g; 5% acetone/CH2CI2) to give a clear and colorless oil. (15 g, 60% yield), MS (ESI): 30 exact mass calculated for C14H11NO2S, 257.1; m/z found, 258.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 7.92 (d, J = 7.4, 1H), 7.69 (d, J= 8.0, 1H), 7,50-7.31 (m, 5H), 7.32 (t, J= 7.5, 1H), 5.32 (t, J= 5.7, 1H), 4.55 (d, J= 5.7, 2H). 171 544938 pct/us2004/024309 C. 2-(4-Chloromethvl-phenoxv)-benzothiazole. To a mixture of [4-(benzothiazol-2-yloxy)-phenyl]-methanol (11 g, 43 mmol) in CH2CI2 (100 mL) containing triethytlamine (9 mL, 65 mmol) at 5°C was added dropwise over 15 minutes thionyl chloride (4 mL g, 55 mmol). The ice bath was removed and the mixture warmed to room temperature and stirred for 24 hr. The mixture was washed once with saturated K2 C03 (100 mL), dried (MgSCU), and concentrated under reduced pressure to give a black oil. The crude oil was purified on Si02 (300 g; 100% CH2CI2) to give a clear orange oil. (10 g, 84% yield). MS (ESi): exact mass calculated for c14h10cinos, 275.0; m/z found, 10 276.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.95 (d, J - 7.3, 1H), 7.70 (d, J = 7.6, 1H), 7.59 (d, J = 8.6, 2H), 7.47 (d, J = 8.6, 2H), 7.37 (t, J = 7.4, 1H), 7.33 (t, J = 7.5, 1H), 4.84 (s, 2H).
D. 3-f1-r4-(Benzothiazol-2-vloxv)-benzvn-piperidin-4-vl)-oxazolidin-2-one. To a mixture of 2-(4-chloromethyl-phenoxy)-benzothiazoie (670 mg, 2.4 mmol) in CH3CN (15 mL) containing K2C03 (544 mg, 3.9 mmol) was added 3-piperidin-4-yk>xazolidin-2-one hydrochloride salt (355 mg, 1.7 mmol) and the mixture was heated to 60 °C for 24 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give the crude product as a golden oil. The crude oil was purified on Si02 (12 g; acetone) to give a white 20 solid (591 mg, 84% yield). MS (ESI): mass calculated for c22h23n3o3s, 409.2; m/z found, 410.3 [M+Hf. 1H NMR (400 MHz, DMSO-de): 7.94 (d, J= 8 7, 1H), 7.70 (d, J = 7.5, 1H), 7.48-7.37 (m, 5H), 7.33 (d, J = 8.0, 1H), 4.25 (t, J = 7.7, 2H), 3.60-3.42 (m, 5H), 2.85 (d, J = 11.5, 2H), 2.04 (t, J =11.4, 2H), 1.78-1.58 (m, 4H).
EXAMPLE 260 4-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-morpholin-3-one. 172 544338 A. 4-Piperidin-4-vl-morpholin-3-one. To a solution of 1-benzyl-4-piperidinone (10.3 g, 54 mmol) and ethanolamine (13.2 mL, 218 mmol) in CH3OH (20 mL) was added sodium cyanoborohydride (10.2 g, 163 mmol) and trifluoromethanesulfonic acid (5 mL) and the reaction mixture was stirred at 23 °C for 3 days. The mixture was cooled to 0 °C and 12 N HCI was slowly added until gas evolution ceased and the resulting mixture was stirred for a further 3 h. The mixture was filtered and the filtrate concentrated. The crude oil was redissolved in H20 (50 mL), and the solution was made basic by the addition of 10 N NaOH. The mixture was extracted with CH2CI2 (8 x 70 mL), The 10 combined CH2CI2 extracts were dried and concentrated under reduced pressure to yield 12.0 g (95% yield) crude product. A 0 °C solution of 2-(1-benzyf-piperidin-4-ylamino)-ethanol (2.13 g, 9.1 mmol) in ethanol (11 mL) and H20 (5 mL) was treated simultaneously with chloroacetyl chloride (1.8 mL, 22.7 mmol) and 35% aq. NaOH solution and the mixture was stirred below 20 °C for 15 3 h. The reaction was diluted with H20 (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried, and concentrated to yield 1.83 g (66% yield) of 4-(1-benzyl-piperidin-4-yl)-morpholin-3-one. To a solution of 4-(1-benzyl-piperidin-4-yi)-morpholin-3-one (1.1 g, 3.9 mmol) in CICH2CH2CI (20 mL) was added a-chioroethyl 20 acetylchloride (660 mg, 4.6 mmol) and the reaction mixture was heated to 100 °C for 16 h. The mixture was cooled to 23 °C and concentrated under reduced pressure. The resulting crude material was purified on Si02 (12 g, 0-10% 2 M ammonia in CH3OH/CH2CI2) to yield 282 mg (53% yield) of 4-piperidin-4-yI-morpholin-3-one. MS (ESI): exact mass calculated for CeH14N202, 184.1; m/z 25 found, 185.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 3.72 (s, 2H), 2.94 (t, J = 6.6, 2H), 2.55 (t, J = 3.6, 2H), 2.46 (tt, J = 10.3, 3.7, 1H), 1.92 (dd, J = 12.3, 2.3, 2H), 1.82-1.70 (m, 2H), 1.70-1.60 (m, 1H), 1.40-1.02 (m, 4H).
B. 441-r4-(Benzothiazol-2-vloxv)-benzvn-piperidin-4-vl)-morpholin-3-one. The titie compound was prepared according to EXAMPLE 259, step D. MS (ESI): exact mass calculated for C24H27N3O3S1, 423.16; m/z found, 424.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8,1, 0.6, 1H), 7.70 (dd, J = 7.9, 0.7, 1H), 7.45-7.40 (m, 2H), 7.36-7.28 (m, 4H), 4.57 (tt, J= 12.1, 4.2, 1H), 4.22 (s, 2H), 3.90 (t, J = 4.9, 2H), 3.56 (s, 2H), 3.34 (t, J = 5.1, 2H), 3.01 (br d, J = 11.6, 2H), 544938 2.18 (ddd, J = 11.7, 11.7, 2.2, 2H), 1.79 (dddd,J= 12.1, 12.1, 12.0, 3.8, 2H), 1.72-1.65 (m,2H).
EXAMPLE 261 OH (R) 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one.
A. (RV 4-Hvdroxv-1"Piperidin-4-vl-pvrro(jdin-2-one acetic acid salt. A solution of 10 4-amino-1-benzylpiperidine (1.0 g, 5.2 mmol) and /V./V-diisopropyiethylamine (2.3 mL, 13.1 mmol) in CH3CN (12 mL) was treated with (R)-4-bromo-3-hydroxybutyrate (1.4 g, 6.8 mmo!) and the mixture was heated at 65 °C for 48 h. The mixture was cooled and diluted with ethyl acetate (70 mL) and washed with H2O (20 mL). The organic layer was dried and concentrated under 15 reduced pressure and the crude residue purified on S1O2 (12 g, 0-5% 2 M ammonia in CH3OH/CH2CI2). The product was dissolved in ethanol (20 mL) and heated to 80 °C for 48 h. The mixture was concentrated under reduced pressure and the crude residue purified on Si02 (12 g, 0-5% 2 M ammonia in CH3OH/CH2CI2) to give 346 mg (25% yield) of 1-(1-benzyl-piperidin-4-yi)-4-20 hydroxy-pyrrolidin-2-one. A solution of 1-(1-benzyl-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one (346 mg, 1.3 mmol) in ethanol (7 mL) was treated with Pd(OH)2 (60 mg) and the mixture charged with hydrogen gas on a Parr apparatus to 50 psi and shaken for 5 days. The mixture was filtered through diatomaceous earth and concentrated to give 280 mg (91% yield) of the title 25 compound, which was used without purification in subsequent reactions. MS (ESI): exact mass calculated for cghienac^, 184.1; m/z found, 185.2 [M+h]+.
B, (R) 1 -(142-f4-fBenzothiazol-2-vioxy)-phenoxv1-ethyl)-piperidin-4-vO-4- hvdroxv-pyrrolidin-2-one. The title compound was prepared according to EXAMPLE 24 using 4-hydroxy-1-piperidin-4-yI-pyrroIidin-2-one acetic acid salt.
MS (ESI): exact mass calculated for C24H27N3O4S1, 453.2; m/z found, 454.5 174 544938 [M+Hf. 1H NMR {400 MHz, CDCI3): 7.77 (dd, J = 8.1, 0,5, 1H), 7.69 {dd, J = 8.0, 0.7, 1H), 7.42 {dt, J = 8.5, 1.3, 1H), 7.34-7.27 (m, 5H), 7.02-6.97 (m, 2H), 4.58-4.53 (m, 1H), 4.18-4.04 (m, 3H), 3.62 {dd, J= 10.7, 5.6, 1H), 3.34 (dd, J = 10.7, 2.2, 1H), 3.15-3.08 (m, 1H), 2.87 (t, J = 5.7, 2H), 2.75 (dd, J= 17.2, 6.6, 5 1H), 2.44 {dd, J = 17.2, 2.6, 1H), 2.34-2,24 (m, 2H), 1.90-1.68 (m, 3H).
EXAMPLE 262 2-{4-{2-[4-{1H-Tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazoie.
A. r4-(Benzothi3zol-2-vloxy)-phenvH-acetaldehvde. A solution of (4-hydroxy-phenyl)-acetic acid methyl ester (11.2 g, 62 mmol) and 2-chlorobenzothiazole (9.5 g mL, 56 mmoi) in CH3CN was treated with finely powdered Cs2C03 (27 g, 84 mmol), and the resulting mixture was stirred at 40 °C for 17 h and 60 °C for 15 2 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude solid was purified by dissolving in ethyl acetate (350 mL) and washing with 10% NaOH (3 x 30 mL), 0.5 M citric acid (1 x 30 mL), sat. aq. NaHC03 (1 x 30 mL), brine (ix 30 mL), then dried over Na2S04, filtered and concentrated under reduced 20 pressure to provide 16 g (95% yield) of [4-(benzothiazol-2-yloxy)-phenyl]-acetic acid methyl ester as a white solid. A solution of [4-(benzothiazol-2-yioxy)~ phenylj-acetic acid methyl ester (5.4 g, 18 mmol) in 80 mL of toluene at -90 °C was treated by dropwise addition of a 1.0 M solution of diisobutyl aluminum hydride in hexanes (27 mL, 27 mmol). The reaction was slowly warmed to -68 25 °C over 30 min and then quenched by the addition of methanol (2.0 mL). The reaction mixture was warmed to -20 °C and diluted with diethyl ether (100 mL) and 2.0 M HCI (60 mL) and stirred vigorously for 30 min. The organic layer was separated, washed with sat. aq. NaHCOa, dried over Na2S04, filtered and concentrated to yield the title compound (4.84 g, 99% yield). n-n 175 544938 B. 2-f4-f2-r4-f1H-Tetrazoi-5-vi)-piperidin-1-vn-ethvll-phenoxv)-benzothiazoie. A solution of [4-(benzothiazol-2-yloxy)-phenyl]-acetaldehyde (628 mg, 2.3 mmol) and 4-(1H-tetrazol-5-yl)-piperidine (443 mg, 2.34 mmol) in CH2CI2 (10 mL) containing triethyiamine (360 jjL, 2.6 mmol) was treated with sodium 5 triacetoxyborohydride (599 mg, 2.7 mmol) and the mixture was stirred at room temperature for 24 h. The mixture was washed with sat. aq. NaHC03 (15 mL), dried (MgSCU), and concentrated under reduced pressure to give a white solid. The solid was washed with diethyl ether and air dried to give the product as a white solid (214 mg, 23% yield). MS (ESI): mass calculated for C21H22N6OS, 10 406.2; m/z found, 407.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.93 (d, J = 7.9, 1H), 7.69 (d, J= 7.7, 1H), 7.48-7.30 (m, 6H), 3.10 (d, J= 11.6, 2H), 3.08-2.97 (m, 1H), 2.87 (t, J = 6.7, 2H), 2.72 (t, J = 8.6, 2H), 2.34 (t, J = 11.0, 2H), 2.01 (d, J = 11.2, 2H), 1.79 (q, J = 9.9, 2H).
EXAMPLE 263 The titie compound was prepared according to the procedure for EXAMPLE 24 20 using piperidin-2-yknethanol. MS (ESI): mass calculated for C21H24N2O3S, 384.2; m/z found, 385.3 [M+Hf, 1H NMR (400 MHz, DMSO-gT6): 7.91 (d, J = 7.9, 1H), 7.68 (d, J = 8.0, 1H), 7.42 (t, J = 7.3, 1H), 7.37 (d, J = 9.0, 2H), 7,31 (t, J = 8.1, 1H), 7.05 (d, J = 9.1, 2H), 4.43 (t, J = 5.3, 1H), 4.08 (t, J = 6.2, 2H), 3.60-3.51 (m, 1H), 3.48-3.39 (m, 1H), 3,17-3.09 (m, 1H), 2.94-2.84 (m, 1H), 25 2.80-2.70 (m, 1H), 2,33 (t, J = 10.4, 2H), 1.62 (d, J = 9.3, 2H), 1.58-1.47 (m, 1H), 1.47-1.35 (m, 1H), 1.35-1.20 (m, 2H).
OH (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidin-2-yl)-methanol. / 176 544938 EXAMPLE 264 N^o (1 -{2-[4-(Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-1 H-tetrazol-5-yl)-acetic acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 24 using (1H-tetrazol-5-yl)-acetic acid ethyi ester. MS (ESI): mass calculated for C20H19N5O4S, 425.1; m/z found, 426.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.91 (d, J = 8.0, 1H), 7.67 (d, J = 7.6, 1H), 7.46-7.36 (m, 3H), 7.32 (t, J = 8.4, 10 1H), 7.03 (d, J = 9.1, 2H), 4.88 (t, J = 5.0, 2H), 4.43 (t, J = 5.0, 2H), 4.35 (s, 2H), 4.14 (q, J = 7.1, 2H), 1.20 (t, J = 7.1, 3H).
EXAMPLE 265 (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3-yl)-methanol.
The title compound was prepared according to the procedure for EXAMPLE 24 using piperidin-3-yl-methanol. MS (ESI): exact mass calculated for C21H24N2O3S1, 384.2; m/z found, 385.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (d, J = 8.1, 1H), 7.68 (d, J = 7.9, 1H), 7.42 (dt, J = 8.4, 1.2, 1H), 7.34-7.26 (m, 3H), 7.02-6.97 (m, 2H), 4.15 (t, J= 5.9, 2H), 3.68 (dd, J= 10.6, 5.2, 1H)t 3.56 (dd, J = 10.4, 6.3, 1H), 3.00 (d, J = 5.3, 1H), 2.84 (t, J = 5.9, 2H), 2.83-2.79 (m, 1H), 2.75-2.60 (m, 1H), 2.30 (t, J = 9.5, 1H), 2.16 (t, J = 9.5, 1H), 1.92-25 1.78 (m,2H), 1.77-1.68 (m, 1H), 1.68-1.60 (m, 1H), 1.24-1.12 (m, 1H). 177 544938 EXAMPLE 266 2-{4-[2-(5-Piperidin-4-yl-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazole hydrochloride.
A. 4-f2-(2-r4-(rBenzothiazoi-2-vloxv)-phenoxy1-ethvl)-2H-tetrazoi-5-v0-piperidine-1-carboxvlic acid tert-butvl ester. To a stirred solution of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (EXAMPLE 9; 500 mg, 1.4 mmol) and 4-(2H-tetrazol-5-yl)-piperidine-1-carboxyIic acid tert-butyl ester (404 mg, 1.6 10 mmol) in CH3CN (10 mL) was added CS2CO3 (537 mg, 1.7 mmoi). The mixture was heated at 60 °C for 20 h and then filtered. The filtrate was concentrated under reduced pressure to a clear goiden oil, which was purified on Si02 (40 g; 0-15% acetone/CH2CI2) to give a white solid (483 mg, 65% yield). TLC (Si02, 15% acetone/CH2CI2): Rf:=0.84. MS (ESI): mass calculated for 15 C26H30N6O4S, 522.2; m/z found, 523.2 [M+Hf. 1H NMR (400 MHz, DMSO-de): 7.90 (d, J = 7.7, 1H), 7.67 (d, J = 7.9, 1H), 7.42 (t, J = 7.1, 1H), 7.36 (d, J = 6.8, 2H), 7.31 (t, J = 8.1, 1H), 7.01 (d, J = 6.9, 2H), 5.05 (t, J = 4.7, 2H), 4.57 (t, J = 4.8, 2H), 3.92 (d, J = 12.4, 2H), 3.20-3.12 (m, 1H), 2.96 (br.s, 2H), 1.97 (dd, J = 13.3, 3, 2H), 1.65-1.52 (m, 2H), 1.40 (s, 9H). 20 B. 2-{4-r2-f5-Piperidin-4-vl-tetrazol-2-yO-ethoxvl-phenoxy)-benzothiazole hydrochloride. To a stirred solution of 4-(2-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-2H-tetrazol-5-yl)-piperidine-1-carboxyIic acid tert-butyl ester (440 mg, 0.84 mmol) in 88% formic acid (7.5 mL) was added concentrated HCI (75 pL, 0.009 mmol). The mixture was stirred at room temperature for 20 h 25 and concentrated under reduced pressure to give a clear, colorless oil. The oil was dried under high vacuum for 2 h and a white solid was obtained (337 mg, 99% yield). MS (ESI): mass calculated for C21H22N6O2S, 422.2; m/z found, 423.3 [M+H]+. 1H NMR (400 MHz, DMSO-de): 7.92 (d, J = 7.9, 1H), 7.67 (d, J = 8.0, 1H), 7.42 (t, J = 7.8, 1H), 7.39 (d, J = 9.4, 2H), 7.32 (t, J = 7.4, 1H), 5.08 30 (t, J = 4.7, 2H), 4.58 (t, J = 4.8, 2H), 3.40-3.22 (m, 4H), 3.03 (q, J = 15.1, 2H), 2.16 (d,J= 14.1, 2H), 1.92 (q, J= 14.3, 2H). 178 544938 EXAMPLE 267 O 7-{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyI}-4-spiro-[3-phthaiide]-piperidine.
The title compound was prepared according to the procedure for EXAMPLE 24 using 4-spiro-[3-phthalide]-piperidine. MS (ESI): mass calculated for C27H24N2O4S, 472.2; m/z found, 473.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 7.92 (d, J = 7.9, 1H), 7.83 (d, J = 7.7, 1H), 7.82-7.75 (m, 2H), 7.70 (d, J = 10.2, 10 1H), 7.61 (t, J = 11.6, 1H), 7.48-7.38 (m, 3H), 7.32 (t, J = 8.2, 1H), 7.10 (d, J = 9.1, 2H), 4.19 (t, J = 5.7, 2H), 3.05 (d, J = 13.0, 2H), 2.86 (t, J = 5.6, 2H), 2.50-2.44 (m, 2H), 2.28 (t, 13.5, 2H), 1.65 (d, J= 12.5, 2H).
EXAMPLE 268 1 -{3-[4-(Benzothiazoi-2-yloxy)-phenyl]-propyi}-piperidine-4-carboxylic acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 35 20 using piperidine-4-carboxylic acid ethyi ester for step A and 2- chtorobenzothiazole for step C. MS (ESI); mass calculated for C24H28N203Sf 424.2; m/z found, 425.3 [M+Hf. 1H NMR (400 MHz, DMSO~of6): 7.92 (d, J = 7.9, 1H), 7.68 (d, J = 8.0, 1H), 7.43 (t, J = 8.1, 1H), 7.38-7.28 (m, 5H), 4.05 (q, J = 7.1, 2H), 2.78 (d, J = 11.3, 2H), 2.63 (t, J = 7.5, 2H), 2.25 (t, J = 7.0, 3H), 25 1.93 (t, J = 13.2, 2H), 1.84-1.68 (m, 4H), 1.54 (q, J = 14.9, 2H), 1.18 (t, J = 7.1, 3H).
O 179 544938 EXAMPLE 269 Qx N x0 nh 2-[4-{Benzothiazol-2-yloxy)-phenyl3-ethylamine hydrochloride.
A. r2-f4-Hvdroxv-phenv0-ethvll-carbamic acid tert-butvl ester. To a stirring solution of di-tert-butyl dicarbonate (34.2 g, 157 mmol) in THF (200 mL) was added tyramine (21.3 g, 155 mmol) in THF (100 mL)over 1 h. The mixture was stirred for 2.5 h and concentrated under reduced pressure to give a clear golden oil which was purified on Si02 (300 g; 0-25% acetone/CH2CI2). The desired fractions were combined and concentrated under reduced pressure to give the product as a clear pink oil (37 g, 100% yield). TLC (Si02, 5% acetone/CH2CI2): Rf=0,31. MS (ESi): mass calculated for C13H19NO3, 237.1; m/z found, 260.2 [M+Naf. 1H NMR (400 MHz, DMSO-ofe): 9.16 (s, 1H), 6.96 (d, J = 8.4, 2H), 6.82 (s, 1H), 6.66 (d, J = 8.4, 2H), 3.05 (q, J = 8.3, 2H), 2.56 (t, J = 8.1, 2H), 1.37 (s, 9H).
B. {2-f4-CBenzothiazol-2-vloxv)-phenvll-ethvl>-carbamic acid tert-butyi ester. The title compound was prepared following the procedure from EXAMPLE 30, step B using [2-(4-hydroxy-phenyl)-ethyi]-carbamic acid tert-butyl ester tp give a white solid (9 g, 56% yield). TLC (Si02, CH2CI2): Rf = 0.19. MS (ESI): mass calculated for C20H22N2O3S, 370.1; m/z found, 371.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.92 (d, J = 7.9, 1H), 7.68 (d, J = 8.0, 1H), 7.48-7.30 (m, 6H), 7.34 (t, J = 7.8, 1H), 3.09 (d, J = 7.1, 2H), 2.75 (t, J = 7.4, 2H), 1.38 (ss 9H).
C. 2-[4-(Benzothiazol-2-vloxv)-phenvll-ethviamine hydrochloride. The title compound was prepared according to the procedure for EXAMPLE 266, step B to give a white solid (6,4 g, 100% yield). MS (ESI): mass calculated for Ci5Hi4N2OS, 270.1; m/z found, 271.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 8.05 (br s, 2H), 7.94 (d, J = 7.8, 1H), 7.68 (d, J = 7.8, 1H), 7.53-7.39 (m, 5H), 7.34 (t, J = 7.9, 1H), 3.09 (t, J = 6.9, 2H), 2.95 (t, J = 8.6, 2H). 180 544938 EXAMPLE 270 HN—fg 2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yi]-ethoxy}-phenoxy)-benzothiazole.
A. r4-(Benzothiazol-2-y[oxv)-phenoxvl-acetic acid methyl ester. To a stirring mixture of sodium hydride (7.5 g, 187,5 mmol) in DMSO (100 mL) was added hydroquinone (10.0 g, 91.2 mmol) over 30 minutes. The mixture was then heated to 80 °C for 2 h and cooled to room temperature. To the stirring mixture was added 2-chlorobenzothiazole (11.3 mL, 91.3 mmol) over 30 10 minutes and the mixture was stirred at room temperature for 24 h. To the mixture was added methyl-2-bromoacetate (8.6 mL, 90.8 mmol) over 30 minutes and the mixture stirred for 24 h. To the mixture was added H2O (1 L) and the product extracted with Et20 (2 x 500 mL), dried (MgSC>4), and concentrated under reduced pressure to give a beige solid. The solid was 15 stirred in CH2CI2 (200 mL) and filtered to give the product as a white solid (24.2 g, 84% yield), MS (ESI): mass calculated for C16H-13NO4S, 315.1; m/z found, 316.2 [M+Hf. 1H NMR (400 MHz, DMSO-tfe): 7.92 (d, J = 8.0, 1H), 7.66 (d, J = 8.1, 1H), 7.47-7.40 (m, 3H), 7.32 (t, J = 7,5, 1H), 7.07 (d, J = 8.6, 2H) 4.87 (s, 2H), 3.73 (s, 3H).
B. f4-(Benzothiazol-2-vloxvVphenoxy1-acetaldehvde. To a stirring solution of [4-(benzothiazol-2-yloxy)-phenoxy]-acetic acid methyl ester (1.0 g, 3.17 mmol) in THF (15 mL) at -78 °C was added DIBAL-H (5 mL, 5 mmol) while maintaining the temperature below -75 °C. The mixture was stirred at -72 °C for 4 h and quenched with H20 (10 mL), extracted with CH2CI2 (2x10 mL), 25 dried (MgS04), and concentrated under reduced pressure to give a clear golden oil (708 mg, 78% yield). MS (ESI): mass calculated for C15H11NO3S, 285,1; m/z found, 286.3 [M+Hf.
C. 2-C4-(2-r4-MH-Tetrazol-5-vlVpiperidin-1-vn-ethoxv)-phenoxv)-benzothiazole. The title compound was prepared according to the procedure for EXAMPLE 30 262, step B using 4-(1H-tetrazol-5-yl)-piperidine. MS (ESI): mass calculated 181 544938 for C2iH22N602S, 422.2; m/z found, 422.3 [M+Hf. 1H NMR (400 MHz, DMSO-£ie): 7.93 (d, J = 7.8, 1H), 7.68 (d, J = 7.9, 1H), 7.49-7.40 (m, 3H)f 7.33 (t, J = 7.3, 1H), 7.14 (d, J = 9.0, 2H), 4.43 (t, J = 4.3, 2H), 3.62-3.43 (m, 4H), 3.25-3.10 (m, 3H), 2.25 (d, J= 12.0, 2H), 2.18-2.02 (m, 2H). 2-(4-Piperidin-1-ylmethyl-phenoxy)-benzooxazoIe.
A. 4-Piperidin-1 -vimethvl-phenol. A mixture of 4-hydroxybenzaldehyde (10 g, 82 mmol), piperidine (16 mL, 164 mmol), and molecular sieves (10 g, crushed, 4A) in CICH2CH2CI (150 mL) was stirred at room temperature for 40 min. To the resulting mixture was added NaBH(OAc)3 portion wise over 1.5 h (7 x 5 g, 164 mmol). The mixture was stirred at room temperature for 24 h. The 15 resulting mixture was diluted with CH2CI2, (300 mL) filtered through diatomaceous earth and rinsed with additional CH2CI2 (100 mL). The filtrate was washed with sat. aq. NaHC03 (3 x 150 mL), and extracted with 25% isopropanol/CHCh, dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a orange semi-solid. The crude product w^as 20 purified on Si02 (120 g; 0-100% acetone/CH2CI2) to give a yellow solid (3.08 g, 48% yield). MS (ESI): mass calculated for C12H17NO, 191.1; m/z found, 192.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.18 (d, J = 8.4, 2H), 6.75 (d, J = 8.4, 2H), 3.83 (s, 2H), 2.81 (br s, 4H), 1.77 (quint, J = 5.7, 4H), 1.54 (br s, 2H). B. 2-C4-Piperidin-1 -vlmethvl-phenoxvVbenzooxazole. The title compound was 25 prepared according to the procedure for EXAMPLE 13, step B using 4-piperidin-1-ylmethyl-phenol. MS (ESI): mass calculated for CigH2oN202S, 308.2; m/z found, 309.4 [M+Hf. 1H NMR (400 MHz, DMSO-cfe); 7.64 (d, J = 3.1 Hz, 1H), 7.52 (d, J= 8.9 Hz, 1H), 7.3 (q, J = 8.3 Hz, 4H), 7.34-7.26 (m, 2H), 3.45 (s, 2H), 2.33 (br.s, 4H), 1.57-1.46 (m, 4H), 1.44-1.32 (m, 2H).
EXAMPLE 271 182 544938 EXAMPLE 272 Q-j^ N^o [4-(Benzothiazol-2-yloxy)-benzyl]-cycIohexyl-ethyI-amine, The title compound was prepared according to the procedure for EXAMPLE 259, step D using cyclohexyl-ethyl-amine. MS (ESI): mass calculated for C22H26N2OSt 366.2; m/z found, 367.4 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.93 (d, J = 8.5, 1H), 7.70 (d, J = 8.0, 1H), 7.45 (t, J = 8.5, 3H), 7.37 (d, J = 8.6, 2H), 7.33 (t, J = 8.3, 1H), 3.63 (s, 2H), 2.58-2.41 (m, 3H), 1.76 (t, J = 11.9, 4H), 10 1.58 (d, J= 12.1, 1H), 1,32-1.01 (m, 5H), 0.95 (t, J-7.1, 3H).
EXAMPLE 273 [4-(Benzothiazol-2-yloxy)-benzyl]-cyciopropyImethyl-propyf-amine, The title compound was prepared according to the procedure for EXAMPLE 259, step D using (2-cyclopropyl-methyl)-ethy!-amine. MS (ESi): mass calculated for C2iH24N2OS, 352.2; m/z found, 353,3 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 7.94 (d, J = 8.0, 1H), 7,70 (d, J = 8.1, 1H), 7.45 (t, J = 8.5, 20 3H), 7.39 (d, J = 8.6, 2H), 7.33 (t, J = 8.0, 1H), 3.66 (s, 2H), 2.53-2.44 (m, 3H), 2.32 (d, J = 6.5, 2H), 1.54-1.42 (no, 2H), 1.32-1.01 (m, 5H), 0.85 (d, J = 7.3, ' 4H), 0.45 (d, J = 9.7, 2H), 0.06 (t, J = 6.2, 2H).
EXAMPLE 274 O 183 544938 1-[4-(Benzothiazol-2-yloxy)~benzy[]-piperidine-4-carboxylic acid amide.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using piperidine-4-carboxylic acid amide. MS (ESi): mass 5 calculated for C20H21N3O2S, 367.1; m/z found, 368.3 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 7.94 (d, J = 7.4, 1H), 7.70 (d, J = 7.9, 1H), 7.48-7.38 (m, 5H), 7.33 (d, J = 7.1, 1H), 7.22 (s, 1H), 6.73 (s, 1H), 3.49 (s, 2H), 2.83 (d, J = 11.4, 2H), 2.14-2.02 (m, 1H), 2.00-1.93 (m, 2H), 1.73-1.62 (m, 2H), 1.58 (t, 15.4, 2H).
EXAMPLE 275 1'-[4-(Benzothiazol-2-yloxy)-benzyl]-[1,4']bipiperidinyl-2-one.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using [1,4'jbipiperidinyJ-2-one. MS (ESI); mass calculated for C24H27N302S, 421.2; m/z found, 422.5 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 7.94 (d, J = 8.8, 1H), 7.70 (d, J = 8.6, 1H), 7.48-7.38 (m, 5H), 7.33 (d, Jp 9.0, 1H), 4.37-4.25 (m, 1H), 3.52 (s, 2H), 3.16 (t, J = 5.2, 2H), 2.89 (d, J =11.2, 2H), 20 2.22 (t, J = 6.6, 2H), 2.03 (t, J = 11.1, 2H), 1.78-1.58 (m, 6H), 1.45 (d, J = 10.8, 2H).
EXAMPLE 276 {4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-pyridin-3-yl-methanone. o 184 544938 The title compound was prepared according to the procedure for EXAMPLE 259, step D using piperazin-1-yl-pyridin-3-yl-methanone. MS (ESI): mass calculated for C24H22N4O2S, 430.2; m/z found, 431.4 [M+H]+. 1H NMR (400 MHz, DMSO-cf6): 8.65 (d, J = 4.8, 1H), 8.61 (d, J = 1.9, 1H), 7.94 (d, J = 7.9, 5 1H), 7.84 (d, J = 7.8, 1H), 7.69 (d, J = 8.0, 1H), 7.60-7.40 (m, 6H), 7.33 (d, J = 8.3, 1H), 3.64 (br s, 2H), 3.58 (s, 2H), 3.37 (br s, 2H), 2.41 (br s, 4H).
EXAMPLE 277 {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4~yimethyl}-carbamic acid tert-butyl ester.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using piperidin-4-ylmethyl-carbamic acid tert-butyl ester. MS (ESI): 15 mass calculated for C25H31N3O3S, 453.2; m/z found, 454.4 [M+H]4. 1H NMR (400 MHz, DMSO-c/e): 7.94 (d, J = 7.3, 1H), 7.70 (d, J- 7.9, 1H), 7.48-7.37 (m, 5H), 7.33 (d, J = 8.2, 1H), 6.85 (t, J = 5.9, 1H), 3.48 (s, 2H), 2.86-2.76 (m, 4H), 1.90 (t, J =11.1, 2H), 1.56 (d, J = 11.8, 2H), 1.37 (s, 10H), 1.11 (t, J = 9.^ 2H).
EXAMPLE 278 o {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yimethyl}-carbamic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 258, step C using methyl chloroformate. MS (ESi): mass calculated for C22H25N3O3S, 411.2; m/z found, 412.4 [M+H]+. 1H NMR (400 MHz, DMSO-c/e): 185 544938 7.94 (d, J = 7.9, 1H), 7.70 (d, J = 8.0, 1H), 7.48-7.36 (m, 5H), 7.33 (d, J = 8.0, 1H), 7.17 (t, J = 5.6, 1H), 3.51 (s, 3H), 3.48 (s, 2H), 2.87 (t, J = 6.2, 2H), 2.80 (d, J =11.1, 2H), 1.90 (t, J= 10.5, 2H), 1.60 (t, J= 12.8, 2H), 1.38 (brs, 1H), 1.20-1.06 (m, 2H).
EXAMPLE 279 Ql jTY^O H o o | 0 H N-{C-[[4-(benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl]-methylamino sulfonyl}-carbamic acid tert-butyl ester To a stirring solution of C-{1-[4-(benzothiazo[-2-yloxy)-benzyl]-piperidin-4-yl}-methylamine (EXAMPLE 258, step B, 657 mg, 1.5 mmol) in CH2CI2 (15 mL) containing triethylamine (1 mL, 7.2 mmol) was added carbamic acid, N-(sulfonyl chloride) tert butyl ester (440 mg, 2.1 mmol). The mixture was stirred 15 for 48 h and brought up in CH2CI2 (50 mL) and washed once with H2O (75 mL), dried (MgS04) and concentrated under reduced pressure to give a clear and colorless oil. The oil was purified on Si02 (12 g, 0-50% acetone/CH2CI2) and the desired fractions combined and concentrated under reduced pressure to give a white solid (112 mg, 14% yield). TLC (Si02s 50% acetone/CH2Ci2): Rf = 20 0.40. MS (ESI): mass calculated for C^H^N^OsS^ 532.2; m/z found, 533.4 [M+Hf. 1H NMR (400 MHz, DMSO-c/e): 10.74 (br s, 1H), 7.90 (d, J= 7.9, 1H), 7.66 (d, J = 8.0, 1H), 7.54 (br s, 1H), 7.44-7.34 (m, 5H), 7.30 (d, J = 8.3, 1H), 3.48 (s, 2H), 2.84-2.70 (m, 4H), 1.90 (t, J =10.4, 2H), 1.64 (d, J = 11.4, 2H), 1.38 (s, 10H), 1.16-1.02 (m, 2H).
EXAMPLE 280 186 544938 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-suifamide hydrochloride The title compound was prepared from EXAMPLE 279 following the procedure 5 for EXAMPLE 266, step B. MS (ESI): mass calculated for C2oH24N403S2, 432.1; m/z found, 433.4 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 10.08 (brs, 1H), 7.80 (d, J= 8.2, 1H), 7.76-7.68 (m, 3H), 7.58 (d, J= 8.6, 2H), 7.45 (t, J = 8.4, 2H), 7.36 (t, J = 8.8, 2H), 6.70-6.50 (br s, 2H), 4.33 (d, J = 5.4, 2H), 3.00-2.86 (br s, 1H), 2.77 (t, J = 6.2, 2H), 1.91 (d, J = 13.4, 2H), 1,71 (br s, 1H), 10 1.50-1.36 (m, 2H), 1.34-1.26 (m, 1H).
EXAMPLE 281 cbjxtxsY o N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 258, step C using acetyl chloride. MS (ESI): mass calculated for c22h25n3o2s, 395.2; m/z found, 396.4 [M+Hf. 1H NMR (400 MHz, DM^O-de): 7.94 (d, J = 7.8, 1H), 7.83 (t, J = 5.5, 1H), 7.70 (d, J = 8,0, 1H), 7.48-7.36 (m, 20 5H), 7.33 (d, J = 8.2, 1H), 3.48 (s, 2H), 2.93 (t, J = 6.2, 2H), 2.81 (d, J = 11.4, 2H), 1.91 (t, J = 11.3, 2H), 1.80 (s, 3H), 1.61 (d, J = 11.0, 2H), 1.38 (br s, 1H), 1.20-1.06 (m, 2H).
EXAMPLE 282 „ OA, {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-acetic acid. 187 544938 The title compound was prepared according to the procedure for EXAMPLE 259, step D using piperidin-4-yl-acetic acid ethyl ester and EXAMPLE 250, step D. MS (ESi): mass calculated for C21H22N2O3S, 382.1; m/z found, 383.4 [M+Hf. 1H NMR (400 MHz, DMS O-cfe): 10.1 (brs, 1H), 7.97 (d, J= 7.9, 1H), 5 7.70 (d, J = 7.6, 3H), 7.58 (br s, 2H), 7.45 (t, J = 7.2, 1H), 7,36 (t, J = 7.3, 1H), 4.31 (br s, 1H), 2.98 (br s, 3H), 2.20 (d, J = 5.6, 3H), 1,87 (br s, 4H), 1.51 (br s, 2H).
EXAMPLE 283 Acetic acid ({1-[4-(benzothiazoi-2-yloxy)-benzyl]-piperidin-4-yimethyl}-carbamoyi)-methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 15 258, step D using acetic acid [(piperidin-4-ylmethyl)-carbamoyi]-methyl ester and EXAMPLE 253, step D. MS (ESI): mass calculated for C24H27N3O4S, 453.2; m/z found, 454.4 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 8.01 (t, J = 5.8, 1H), 7.94 (d, J= 7.5, 1H), 7.70 (d, J = 8.0, 1H), 7.80-7.36 (m, 5H), 7.33 (t, J = 7.2, 1H), 4.43 (s, 2H), 3.48 (s, 2H), 2.98 (t, J = 6.3, 2H), 2.81 (d, J = 11.4, 20 2H), 2.08 (s, 3H), 1.91 (t, J = 11.2, 2H), 1.60 (d, J = 11.2, 2H), 1.42 (br s, 1H), 1.20-1.08 (m, 2H).
EXAMPLE 284 [2-({1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyi}-carbamoyl)-cyciobutylj-carbamic acid tert-butyl ester. 188 O 544938 The title compound was prepared from EXAMPLE 258, step B following EXAMPLE 257, step C using 2-tert-butoxycarbonylamino-cyclobutanecarboxylic acid. MS (ESI): mass calculated for C30H38N4O4S, 5 550.3; m/z found, 551.5 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.94 (d, J ~ 7.9, 1H), 7.70 (d, J = 8.0, 1H), 7.47-7.35 (m, 7H), 7.33 (t, J- 7.3, 1H), 3.47 (s, 2H), 2.95 (t, J = 6.1, 2H), 2.78 (t, J = 9.6, 2H), 2.45-2.35 (m, 2H), 2.13 (s, 1H), 2.05-1.95 (m, 2H), 1.93-1.70 (m, 4H), 1.59 (d, J = 10.9, 2H), 1.38 (s, 9H), 1.20-1.05 (m, 2H).
EXAMPLE 285 2-Amino-cyclobutanecarboxylic acid {1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-amide dihydrochloride.
The title compound was prepared according to the procedure for EXAMPLE 266, step B. MS (ESI): mass calculated for C25H30N4O2S, 450.2; m/z found, 451.4 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 8.78-8.55 (m, 4H), 7.97 (^ J = 8.1, 1H), 7.78 (d, J = 8.6, 3H), 7.71 (d, J=7.8, 1H), 7.45 (t, J = 8.5, 1H), 7.36 20 (t, J = 7.1, 1H), 4.32 (s, 2H), 3.20-3.05 (m, 2H), 3.00-2.85 (m, 2H), 2.472 (d, J = 4.7, 2H), 2.62-2.50 (m, 2H), 2.65-2.42 (m, 2H), 2.38-2.05 (m, 1H), 2.02-1.70 (m, 6H), 1.68-1.50 (s, 2H).
EXAMPLE 286 2-(4-Pyrrolidin-1-ylmethyl-phenoxy)-benzothiazole. 189 544938 The title compound was prepared according to the procedure for EXAMPLE 259, step D using pyrrolidine. MS (ESI): mass calculated for CigH^^OS, 310.1; m/z found, 311.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.94 (d,J = 9.0, 1H), 7.70 (d, J = 8.0,-1 H), 7.48-7.37 (m, 5H), 7.33 (t, J= 7.7, 1H), 3.62 (s, 5 2H), 2.49-2.40 (m, 4H), 1.78-1.65 (m, 4H).
EXAMPLE 287 %^OT" 2-{[4-(Benzothiazol-2-yloxy)-benzyl]-ethyl-amino}-ethanol.
The titie compound was prepared according to the procedure for EXAMPLE 259, step D using 2-ethylamino-ethanol. MS (ESI): mass calculated for Ci8H2oN202S, 328.1; m/z found, 329.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.94 (d, J = 8.0, 1H), 7.70 (d, J = 7.7, 1H), 7.50-7.36 (m, 5H), 7.33 (t, J = 7.7, 15 1H), 4.39 (t, J - 5.4, 1H), 3.63 (s, 2H), 3.49 (q, J = 6.4, 2H), 2.57-2.45 (m, 4H), 1.00 (t, J = 7.1,3H).
EXAMPLE 288 2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-2-yl}-ethanoi.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using 2-piperidin-2-yl-ethanol. MS (ESI): mass calculated for C2iH24N202S( 368.2; m/z found, 369.4 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 25 7.93 (d, J = 8.0, 1H), 7.70 (d, J = 7.7, 1H), 7.48-7.36 (m, 5H), 7.33 (t, J - 6.9, 1H), 4.42 (s, 1H), 3.92 (d, J- 14.0, 1H). 3.50 (brs, 2H), 3.31 (d, J= 6.4, 1H), 2.70-2.60 (m, 1H), 2.14-2.03 (m, 1H), 1.87-1.75 (m, 1H), 1.70-1.55 (m, 3H), 1.53-1.27 (m, 5H). 190 544938 EXAMPLE 289 r o 1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-ethanone.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using 1-piperazin-1-yl-ethanone. MS (ESI): mass calculated for C20H21N3O2S, 367.1; m/z found, 368.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 7.94 (d, J = 8.0, 1H), 7.70 (d, J = 7.5, 1H), 7.48-7.39 (m, 5H), 7.33 (t, J = 7.7, 10 1H), 3.55 (s, 2H), 3.50-3.40 (m, 4H), 2.40 (t, J = 4.9, 2H), 2.33 (t, J = 5.0, 2H), 1.99 (s, 3H).
EXAMPLE 290 8-[4-(Benzothiazol-2-yloxy)-benzyl]-2,8-diaza-spiro[4.5]decan~l-one.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using 2,8-diaza-spiro[4.5]decan-1 -one. MS (ESI); mass calculated for C22H23N302S, 393.2; m/z found, 394.3 [M+Hf. 1H NMR (400 20 MHz, DMSO-cfe): 7.94 (d, J = 7.4, 1H), 7.70 (d, J = 8.0, 1H), 7.54 (s, 1H), 7.48-7.36 (m, 5H), 7.33 (t, J= 8.2, 1H), 3.51 (s, 2H), 3.15 (t, J = 6.8, 2H), 2.75(d, J = 11.6, 2H), 2.05 (t, J = 10.0, 2H), 1.91 (t, J = 6.8, 2H), 1.70 (t, J - 12.6, 2H), 1.33 (d, J= 12.8, 2H). 191 544938 EXAMPLE 291 Q* N O O Spiro[isobenzofuran-1 (3H), 4'-piperidin]-3-one, 1 '-[4-(BenzothiazoI-2-yloxy)-benzyi] The title compound was prepared according to the procedure for EXAMPLE 259, step D using spiro[isobenzofuran-1(3H), 4'-piperidin]-3-one. MS (ESI): mass calculated for C26H22N203S, 442.1; m/z found, 443.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.95 (d, J= 7.9, 1H), 7.83 (d, J = 7.6, 1H), 7.82-7.76 (m, 10 2H), 7.70 (d, J = 8.0, 1H), 7.61 (t, J = 7.8, 1H), 7.56-7.48 (m; 2H), 7.47-7.40 (m, 3H), 7.33 (t, J = 7.4, 1H), 3.66 (s, 2H), 2.90 (d, J = 11.1, 2H), 2.41 (t, J = 11.0, 2H), 2.28 (t, J = 13.3, 2H), 1.66 (d, J = 12.6, 2H).
EXAMPLE 292 (R)-1 -[4-(Benzothiazol-2-yloxy)-benzyl]-pyrro!idin~3-ol. 1 The title compound was prepared according to the procedure for EXAMPLE 259, step D using (R)-pyrrolidin-3-ol. MS (ESI): mass calculated for 20 C18HisN202S, 326.1; m/z found, 327.2 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.94 (d, J = 8.0, 1H), 7.70 (d, J = 8.1, 1H), 7.48-7.36 (m, 5H), 7.33 (t, J = 7.2, 1H), 4.72 (d, J = 4.5, 1H), 4.27-4.16 (m, 1H), 3.60 (q, J = 13.2, 2H), 2.73-2.65 (m, 1H), 2.60 (q. J = 8.1, 1H), 2.47-2.38 (m, 1H), 2.36-2.30 (m, 1H), 2.07-1.95 (m, 1H), 1.62-1.50 (m, 1H). 192 544938 EXAMPLE 293 Qx 6 2-[4-(2-Methyl-piperidin-1-ylmethyl)-phenoxy]-benzothiazoie.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using 2-methyl-piperidine, MS (ESi): mass calculated for C20H22N2OS, 338.2; m/z found, 339.3 [M+Hf. 1H NMR (400 MHz, DMSO-of6): 7.94 (d, J = 8.0, 1H), 7.70 (d, J = 8.1, 1H), 7.30-7.33 (m, 5H), 7.33 (t, J = 7.9, 1H), 3.96 (d, J= 13.9, 1H), 3.19 (d, J= 13.9, 1H), 2.70-2.60 (m, 1H), 2.40-2.30 10 (m, 1H), 1.98 (t, J= 13.0, 1H), 1.68-1.56 (m, 2H), 1.54-1.34 (m, 2H), 1.32-1,24 (m, 2H), 1.11 (d, J = 6.2, 3H).
EXAMPLE 294 [4-(Benzothiazol-2-yloxy)-benzyl]-diethyl-amine.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using diethylamine. MS (ESI): mass calculated for C-ia^o^OS, 312.1; m/z found, 313.3 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 7.94 (d,J = 20 7.9, 1H), 7.70 (d,J = 8.0, 1H), 7.48-7.36 (m, 5H), 7.33 (t, J= 7.2, 1H), 3.57 (s, 2H), 2.48 (q, J = 7.1, 4H), 1.00 (t, J - 7.1, 6H).
EXAMPLE 295 [4-(Benzothiazol-2-yloxy)-benzyl]-butyl-methyl-amine.. 193 544938 The title compound was prepared according to the procedure for EXAMPLE 259, step D using butyl-methyl-amine. MS (ESI): mass calculated for C19H22N2OS, 326.2; m/z found, 327.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.94 (d, J= 7.9, 1H), 7.70 (d, J= 7.5, 1H), 7.48-7.36 (m, 5H), 7.33 (t, J= 8.0, 5 1H), 3.49 (s, 2H), 2.34 (t, J = 7.1, 2H), 2.13 (s, 3H), 1.50-1.40 (m, 2H), 1.38-1.24 (m, 2H), 0.88 (t, J=7.3, 3H).
EXAMPLE 296 2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-ethanol.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using 2-piperidin-4-yl-ethanoi. MS (ESI): mass calculated for C21H24N202S, 368.2; m/z found, 369.4 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 15 7.74 (d, J = 7.9, 1H), 7.49 (d, J = 8.0, 1H), 7.30-7.16 (m, 5H), 7.13 (t, J = 7.9, 1H), 4.13 (t, J = 5.1, 1H), 3.27 (s, 2H), 3.23 (q, J = 6.2, 2H), 2.59 (d, J = 11.11 2H), 1.72 (t, J=10.3, 2H), 1.42 (d, J = 12.1, 2H), 1.16 (t, J = 3.8, 3H), 1.00-0.85 (m, 2H). 1-[4-{Benzothiazol-2-yloxy)-benzy!]-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 25 259, step D using piperidin-4-ol. MS (ESI); mass calculated for Cig^oN^S, 340.1; m/z found, 341.3 [M+Hf. 1H NMR (4.00 MHz, DMSO-c/6): 7.94 (d ,J = 7.9, 1H), 7.68 (d, J = 8.0, 1H), 7.46-7.36 (m, 5H), 7.32 (t, J= 8.1, 1H), 4.60 (df J = 4,9, 1H), 3.58-3.40 (m, 3H), 2.80 (d, J = 9.9, 1H), 2.65 (d, J- 10.7, 1H), EXAMPLE 297 194 544938 1.87 (t, J = 9.2, 1H), 1.80 (d, J = 8.6, 1H), 1.71 (t, J = 9.8, 1H), 1.62 (d, J = 13.3, 1H), 1.48-1.38 (m, 1H), 1.12-1.00 (m, 1H).
EXAMPLE 298 {1-[4-(Benzothiazol-2-yloxy)~benzyl]-piperidin-2~yl}-methanoI.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using piperidin-2-yi-methanoI. MS (ESI); mass calculated for 10 C20H22NZO2S, 354.1; m/z found, 355.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.98 (d, J= 7.2, 1H), 7.74 (d, J= 8.0, 1H), 7.53-7.42 (m, 5H), 7.37 (t, J = 8.3, 1H), 4.60 (t,J= 5.2, 1H), 4.18 (d, J= 14.1, 1H), 3.75-3.65 (m, 1H), 3.56-3.46 (m, 1H), 3.37 (d, J = 3.8, 1H), 2.72 (d, J = 11.9, 1H), 2.36 (d, J = 4,8, 1H), 2.07 (t, J = 9.7, 1H), 1.72 (t, J = 13.2, 2H), 1.58-1.26 (m, 4H).
EXAMPLE 299 (R)-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-pyrrolidin-2-yI}-methanoI.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using (R)-pyrrolidin-2-yl-methanol. MS (ESI): mass calculated for C1gH2oN202Sl 340.1; m/z found, 340.1 [M+Hf. 1H NMR (400 MHz, DMSO-de): 7.97 (d, J = 7.2, 1H), 7.73 (d, J = 7.8, 1H), 7.50-7.38 (m, 5H), 7.36 (t, J = 7.9, 1H), 4.90 (t, J = 5.4, 1H), 4.14 (d, J= 13.4, 1H), 3.55-3.48 (m, 1H), 3.42 (d, J = 25 13.4, 2H), 2.84 (t, J = 6.6, 1H), 2.68-2.58 (m, 1H), 2.20 (q, J = 8.6, 1H), 1.95-1.83 (m, 1H), 1.72-1.55 (m, 3H).
OH 195 544938 EXAMPLE 300 2-(4-Azetidin-1-yImethyl-phenoxy)-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using azetidine. MS (ESI): mass calculated for C17H16N2OS, 296.1; m/z found, 297.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.80 (d, J = 8.5, 1H), 7.56 (d, J = 8.0, 1H), 7.35-7.24 (m, 5H), 7.19 (t, J = 7.3, 1H), 3.43 (s, 2H), 3.02 (t, J = 7.0, 4H), 1.92-1.80 (m, 2H).
EXAMPLE 301 1 -[4-(Benzothiazol-2-yloxy)-benzyi]-[1,4]diazepan-5-one.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using [1,4]diazepan-5-one. MS (ESI): mass calculated for C19Hi9N302S, 353.1; m/z found, 354.3 [M+Hf. 1H NMR (400 MHz, DM^O-c/s): 7.94 (d, J = 7.9, 1H), 7.69 (d, J = 7.9, 1H), 7.57 (t, J = 5.4, 1H), 7.44-7.33 (m, 5H), 7.33 (t, J = 8.2, 1H), 3.62 (s, 2H), 3.18-3.10 (m, 2H), 2.58-2.40 (m, 6H).
EXAMPLE 302 {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-3-yl}-methanoI.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using piperidin-3-yi-methanol. MS (ESI): mass calculated for 196 544938 C20H22N2O2S, 354.1; m/z found, 355.3 [M+Hf. 1H NMR (400 MHz, DMSO-cfe): 7.98 (d, J= 7.2, 1H), 7.74 (d, J= 7.9, 1H), 7.50-7.42 (m, 5H)( 7.38 ft, J= 8.2, 1H), 4.46 (t, J = 5.3, 1H), 3.52 (d, J = 3.4, 2H), 3.36-3.29 (m, 1H), 3.27-3.18 (m, 1H), 2.92 (d, J = 8.1, 1H), 2.77 (d, J=10.8, 1H), 1.96 (d, J = 12.8, 1H), 1.75-5 1.60 (m, 4H), 1.58-1.45 (m, 1H), 1.00-0.85 (m, 1H).
EXAMPLE 303 1 -[4-(Benzothiazol-2-yloxy)-benzyl]~piperidine-3-carboxylic acid amide.
The title compound was prepared according to the procedure for EXAMPLE 259, step D using piperidine-3-carboxylic acid amide. MS (ESI): mass calculated for C20H21N3O2S, 367.1; m/z found, 368.4 [M+Hf. 1H NMR (400 MHz, DMSO-de): 7.70 (d, J- 7.8, 1H), 7.46 (d, J= 8.0, 1H), 7.25-7.00 (m, 7H), 15 6.53 (s, 1H), 3,26 (d,J = 2.9, 2H), 2.57 (d,J= 10.3, 1H), 2.49 (d, J- 11.3, 1H), 2.15-2.00 (m, 1H), 1.78 (t, J = 10.7, 1H), 1.69 (t, J = 9.4, 1H), 1.51 (d, J=10.0, 1H), 1.40 (d, J = 12.9, 1H), 1.22 (q, J = 12.6, 1H), 1.09 (q, J - 12.2, 1H).
EXAMPLE 304 9-[4-(Benzothiazol-2-yloxy)-benzyl]-3,9-diaza-spiro[5,5]undecane-3-carboxyiic acid tert-butyl ester.
The title compound was prepared according to the procedure for EXAMPLE 25 259, step D using 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. MS (ESI): mass calculated for C28H35N3O3S, 493.2; m/z found, 494.5 [M+Hf. 1H NMR (400 MHz, DMSO-ofe): 8.13 (d, J = 7.9, 1H), 7.89 (d, J= 8.0, 197 544938 1H), 7.68-7.56 (m, 5H), 7.53 (t, J = 7.1, 1H), 3.70 (s, 2H), 3.51-3.45 (m, 4H), 2.60-2.50 (m, 4H), 1.66 (t, J = 5.3, 4H), 1.58 (s, 9H), 1.54 (t, J = 5.4, 4H).
EXAMPLE 305 2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-3-yI}-ethanol.
The titie compound was prepared according to the procedure for EXAMPLE 259, step D using 2-piperidin-3-yl-ethanoi. MS (ESI): mass calculated for 10 C21H24N2O2S, 368.2; m/z found, 369.4 [M+Hf. 1H NMR (400 MHz, DMSO-ofe): 7.71 (d, J = 8.4, 1H), 7.47 (d, J = 7.9, 1H), 7.25-7.15 (m, 5H), 7.10 (t, J = 8.1, 1H), 4.12 (t, J = 5.1, 1H), 3.33-3.15 (m, 4H), 2.58-2.42 (m, 2H), 1.67 (t, J = 9.6, 1H), 1.53-1.33 (m, 4H), 1.30-1.00 (m, 3H), 0.70-0.58 (m, 1H).
EXAMPLE 306 O cis-4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxylic acid trifluoromethanesulfonate salt.
The title compound was prepared according to the procedure for EXAMPLE 262, step B using cis-4-amino-cyclohexanecarboxylic acid. MS (ESI): exact mass calculated for C22H24N2O3S, 396.2; m/z found, 397.3 [M+H]+. 1H NMR (400 MHz, CDCIg): 9.15, (s, 1H), 7.75 (d, J = 7.6, 1H), 7.72 (dd, J = 8.0, 0.7, 1H), 7.43 (dt, J = 7.2, 1.2, 1H), 7.37-7.29 (m, 5H), 5.10 (br s, 1H), 3.29 (br s, 2H), 3.10 (t, J = 7.4, 3H), 2.73 (br s, 1H), 2.24 (br d, J = 10.6, 2H), 2.09 (br d, J = 9.3, 2H), 1.72-1.52 (m, 3H). 198 544938 EXAMPLE 307 /TV ^ -N. 0 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyI}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone.
A. 2-r4-(2-Piperazin-1-vl-ethvD-phenoxy1-benzothiazoie bis trifiuoromethane sulfonate. 4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethy!}-piperazine~1-carboxylic acid tert-butyl ester was prepared according to Example 262, step B, using piperazine-1-carboxylic acid tert-butyl ester. A solution of 4-{2~[4-10 (benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazine-1-carboxy!ic acid tert-butyl ester {3.9 g, 8.9 mmol) in CH2CI2 (5 mL) with a solution of 50% trifluoromethansulfonic acid in CH2CI2 {35 mi) and stirring at 23 °C for 4h. The reaction was concentrated and the residue suspended in diethyl ether, filtered and dried to give the title compound as a white solid {5.4 g, 94% yield). MS 15 (ESI): exact mass calculated for C1gH2iN30iSi, 339.1; m/z found, 340.4 [M+H]+, 1H NMR (400 MHz, D6-DMSO): 9.50-9.30 (br. s, 1H), 7.94 (dd, J=7.9, 0.6, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.48-7.41 (m, 5H), 7.39-7.30 (m, 1HJ.4.15-3.50 (br. s, 1H), 3.45-3.32 (m, 8H), 3.32-3.20 (m, 2H), 3.01 (dd, J= 8.8, 5.2 Hz, 2H).
B. (4-f2-F4-(Benzothiazol-2-vloxvVphenvn-ethv[>-piperazin-1-vi>{tetrahvdro-furan-2-vO-methanone. The title compound was prepared according to the procedure for Example 257 step C, using tetrahydro-furan-2-carboxylic acid and triethylamine. MS (ESI): exact mass calculated for C24H27N3O3S, 437.2; m/z found, 438.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.77 (d, J= 7^3, 1H), 25 7.71 (dd, J = 7.8, 0.8, 1H), 7.42 (dt, J = 7.3, 1.2, 1H), 7.33-7.26 (m, 5H), 4.65 (dd, J = 7.0, 5.3, 1H), 3.99 (ddd, J = 7.7, 7.1, 6.7, 1H), 3.92-3.86 (m, 1H), 3.82-3.72 (m, 2H), 3.76 (s, 1H), 3.70-3.58 (m, 2H), 2.90 (dd, J = 10.3, 7.3, 2H), 2,70 (dd, J = 8.6, 5.6, 2H), 2.64-2.54 (m, 3H), 2.38-2.28 (m, 1H), 2.14-1.90 (m, 4H). 199 544938 pct/us2004/024309 EXAMPLE 308 9 o, ,0 Propane-2-sulfonic acid (1 -{2-[4-(benzothiazoi-2-yioxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amide.
A solution of 1-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid amide (Example 22, 197 mg, 0.5 mmol) in THF (5 mL) was treated with NaH (14 mg, 0.6 mmot) and isopropylsulfonyl chloride (86 mg, 0.6 mmol) and the reaction was stirred at 60 °C for 16 h. The reaction was cooled 10 and quenched by the addition of CH3OH (5 mL) follwed by H2O (5 mL)and the pH was adjusted to pH 7. The solution was extracted with ethyl acetate (2 x 25 mL) and the ethyl acetate solution was washed with 1 M NaOH (2 x 30 mL). The combined base washes were neutralized by the addition of 2 M HCI and extracted with chloroform (2 x 30 mL). The chloroform solutions were dried 15 over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified on SiC>2 (4 g, 0-10% 2 M NHs/CHsOHiC^Ch) to give the title compound as a solid (45 mg, 18% yield). MS (ESI): exact mass calculated for C24H29N3O5S2, 503,2; m/z found, 504,5 [M+H]+. 1H NMR (400 MHz, C6D6): 7.77 (d, J= 7.8, 1H), 7.20 (dd, J = 8.0S 0.8, 1H), 7.16-7.10|m, 20 2H), 7.07 (dt, J = 8.3, 1.0, 1H), 6.90 (dt, J = 8.0, 1.0, 1H), 6.76 (d, J = 8.8, 1H), 6.13 (s, 1H), 3.98 (br s, 2H), 3.51 (sept., J = 6.8, 2H), 3.20 (br s, 2H), 2,82 (br s, 1H), 2.37-2.00 (m, 4H), 1.96-1.84 (m, 2H), 1.33 (d, J = 6,6, 6H) 1.38-1.28 (m, 2H).
EXAMPLE 309 .0.
O 200 544938 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yI)-oxo-acetic acid methyl ester.
A solution of 2-[4-(2-piperazin-1-yl-ethyl)-phenoxy]-benzothiazole bis-5 trifiuoromethane sulfonate (296 mg, 0.52 mmol) in CH2CI2 (3 mL) was treated with triethylamine (0.25 mL, 1.8 mmol), followed by addition of methyl chlorooxoacetate (0.07 mL, 0.8 mmol) and the reaction was stirred at 23 °C for 20 min. The reaction was diluted with CH2Cl2 (10 mL) and washed with sat. aq. NaHC03(10 mL). The organic layer was dried over Na2S04, filtered and 10 concentrated under reduced pressure to give the title compound (234 mg, 99% yield). MS (ESI): exact mass calculated for C22H23N3O4S, 425.1; m/z found, 426.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.76 (d, J= 7.6, 0.5, 1H), 7.70 (d, J = 7.8, 1H), 7.41 (dt, J = 7.3, 1.0, 1H), 7.34-7.26 (m, 5H), 3.91 (s, 3H), 3.72 (t, J = 4.8, 2H), 3.51 (t, J = 4.8, 2H), 2.86, (dd, J = 10, 6.8, 2H), 2.70, (dd, J = 8.6, 15 5.6, 2H), 2.62-2.57 (m, 4H).
EXAMPLE 310 N-(1-{2-[4-(Benzothiazol-2-y!oxy)-pheny!]-ethy!}-piperidine-4-carbonyl)-20 benzenesulfonamide trifluoromethanesulfonate salt.
The title compound was prepared according to the procedure for Example 34, step B using benzene sulfonamide. MS (ESI): exact mass calculated for C27H27N3O4S2, 521.1; m/z found, 522.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 25 8.60-8.00 (m, 2H), 7.82-7.76 (m, 1H), 7.73-7.57 (m, 4H), 7.48-7.28 (m, 5H), 3.70 (brs, 1H), 3.41-3.34 (m, 2H), 3.14-2.98 (m, 3H), 2.60 (brs, 1H), 2.08 (br d, J = 13.6, 2H), 1.86 (br s, 2H) 1.30 (br s, 2H), 0.94-0.88 (m, 2H). 201 544938 EXAMPLE 311 H N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyt]-ethyl}-piperidine-4-carbonyl)-methanesulfonamide trifluoromethanesulfonate salt.
The title compound was prepared according to the procedure for EXAMPLE 34, step B using methane sulfonamide, MS (ESI); exact mass calculated for C22H25N3O4S2, 459.1; m/z found, 460.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.81 (d, J = 7.8, 1H), 7.62 (d, J = 8.1, 1H) 7.49-7.43 (m, 3H), 7.43-7.38 (m, 2H) 10 7.34 (t, J- 7.8, 1H), 3.80 (brd, J~ 10.4, 1H), 3,48-3.40 (m, 2H), 3.33 (s, 3H), 3.28 (s, 2H), 3.20-3.04 (m, 3H), 2.70-2.60 (m, 1H), 2.21 (brd, J= 12.4, 2H), 2.06-1.93 (m,2H).
EXAMPLE 312 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-oxo-acetic acid trifluoromethanesulfonate salt.
The titie compound was prepared according to the procedure for Example 253, stepD. MS (ESI): exact mass calculated for C2iH2iN304St 411.1; m/z found, 412.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.75 (t, J = 8.3, 2H), 7.70 (dt, J = 8.0, 0.8, 1H), 7.28-7.22 (m, 5H), 4.28-3.88 (br m, 4H), 3,58-3.20 (brm, 6H), 3.16-3.04 (brm, 2H).
// O 202 544938 EXAMPLE 313 T O (4-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyI}-piperazin-1-yl)-morpholin-4-yl-methanone.
A solution of 2-[4-(2-piperazin-1-yl-ethyi)-phenoxy]-benzothiazole bis trifluoromethane sulfonate Example 307, step A (268 mg, 0,47 mmol) in CH2CI2 (6 mL) was treated with PS-dimethylamine resin (1.3 g, 0.90 mmol) followed by 4-morpholine carbonyl chloride (0.07 mL, 0.6 mmol) and the reaction shaken 10 for 1h. The reaction was treated with PS-isocyanate resin to scavenge excess isocyanate and after 15 min, the reaction was filtered and concentrated to give the title compound (225 mg, 99% yield). MS (ESI): exact mass calculated for C24H28N403S1, 452.2; m/z found, 453.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.0, 0.5, 1H), 7.71 (dd, J = 7,8, 0,5, 1H), 7.42 (dt, J = 7.3, 1.2, 15 1H), 7.34-7.28 (m, 5H), 3.78-3.70 (m, 4H), 3.39 (br t, J = 4.3, 4H), 3.31 (t, J = 4.8, 4H), 2.90 (dd, J - 10.4, 7.3, 2H), 2.70 (dd, J = 8.3, 7.3, 2H), 2.59 (br s, 4H).
EXAMPLE 314 1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-2-thiophen-2-yl-ethanone The title compound was prepared according to the procedure for EXAMPLE 25 313 using 24hiopheneacetyl chloride. MS (ESI); exact mass calculated for C25H25N303S2, 463.1; m/z found, 464.3 [M+Hf. 1H NMR (400 MHz, CDCI3): O.
O 203 544938 7.77 (dd, J = 8.0, 0.5, 1H), 7.71 (dd, J = 7.8, 0.8, 1H), 7.43 (dt, J = 7.3, 1.2, 1H), 7.34-7.28 (m, 5H), 7.25 (dd, J = 5.3, 1.2, 1H), 7.00 (dd, J = 5.0, 3.2, 1H), 6.96-6.93 (m, 1H), 3.96 (d, J = 0.8, 2H), 3.74 (t, J = 4.8, 2H), 3.59 (t, J - 4.8, 2H), 2.86 (dd, J = 10.4, 7.6, 2H), 2.66 (dd, J = 8.3, 5.6, 2H), 2.55 (t, J = 5.3, 5 2H), 2.47 (t, J = 5.0, 2H).
EXAMPLE 315 0 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-pyridin-3-yl-10 methanone.
The title compound was prepared according to the procedure for EXAMPLE 313 using 2-nicotonyl chloride-hydrochloride. MS (ESI): exact mass calculated for c25h24N402s, 444.2; m/z found, 445.4 [M+H]+. 1h NMR (400 MHz, CDCI3): 15 8.73-8.70 (m, 2H), 7.81 (dt, J = 7.9, 1.9, 1H), 7.77 (dd, J = 8.1, 0.5, 1H), 7.71 (ddd, J- 7.9, 0.7, 0.4, 1H), 7.45-7,39 (m, 2H), 7.34-7.28 (m, 5H), 3.90 (brs, 2H), 3.52 (br s, 2H), 2.92-2.85 (m, 2H), 2.71 (dd, J = 8.9, 5.6, 2H), 2.74-2.60 (m, 2H), 2.54 (brs, 2H). / EXAMPLE 316 0 (4_{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-cyc!opropyl-methanone.
The title compound was prepared according to the procedure for EXAMPLE 313 using cyclopropane carbonylchloride, MS (ESI): exact mass calculated 204 544938 for C23H25N3O2S, 407.2; m/z found, 408,3 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.77 (dd, J = 8.1, 0.5, 1H), 7.71 (dd, J = 7,9, 0.8, 1H), 7.43 (dt, J = 7.4, 1.3, 1H), 7.34-7.28 (m, 5H), 3.74 (d, J= 16.0, 4H), 2,89 (dd, J = 9.4, 6.5, 2H), 2.70 (dd, J = 9.4, 6.5, 2H), 2.58 (br d, J = 20.8, 4H), 1.78 (tt, J = 8.0, 4.7, 1H), 1.06-5 1.01 (m, 2H), 0.83-0.78 (m, 2H).
EXAMPLE 317 o 1-(4-{2-[4-(BenzothiazoI-2-yloxy)-phenyl]-ethyi}-piperazin-1-yl)-2-methoxy-10 ethanone.
A solution of 2-[4-(2-piperazin-1-yl-ethy!)-phenoxy]-benzothiazoie bis trifiuoromethane sulfonate Example 307, step A (200 mg, 0.35 mmol) in CHCI3 (14 mL) was treated with PS-dimethylamine resin (740 mg, 1.0 mmol) and the 15 reaction shaken for 1h. The resin was filtered, and the resulting solution of free base was treated with methoxy acetic acid (0.04 ml, 0.5 mmol) and PS-carbonyl diimidazole resin (500 mg, 0.6 mmol) and the reaction shaken for 1 h. The reaction was filtered and concentrated and the crude product was purified on Si02 (12 g, 0-10% 2M NH3/MeOH : CH2CI2) to give the title compound (143 20 mg, 99% yield). MS (ESI): exact mass calculated for C22H25N3O2S, 411.2; m/z found, 412.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.1, 0.6, 1H), 7.71 (dd, J = 7.9, 0.8, 1H), 7.42 (dt, J = 7.5, 1.3, 1H), 7.35-7.28 (m,5H), 4.14 (s, 2H), 3,72 (t, J = 4.8, 2H), 3.58 (t, J - 4.8, 2H), 3.47 (s, 3H), 2.89 (dd, J = 10.6, 7.3, 2H), 2.70 (dd, J = 8.5, 5.6, 2H), 2.58 (t, J = 5.1, 4H). .0. 205 544938 EXAMPLE 318 ^n^cf3 r o l-^-^-^-fBenzothiazol^-yloxyJ-phenylJ-ethyl^piperazin-l-yO^^-trifluoro-etharione.
The title compound was prepared according to the procedure for EXAMPLE 317 using trifluromethanesulfonic acid. MS (ESI): exact mass calculated for C21H20F3N3O2S, 435.1; m/z found, 436.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.2, 0.5, 1H), 7.71 (dd, J = 7.9, 0.7, 1H), 7.43 (dt, J = 8.5, 1.2, 10 1H), 7.35-7.28 (m, 5H), 4.14 (s, 2H), 3.76 (t, J = 4.8, 2H), 3.68 (t, J = 4.7, 2H), 2.88 (dd, J = 10.0, 7.0, 2H), 2.70 (dd, J = 8.7, 5.6, 2H), 2.62 (t, J = 4.6, 4H).
EXAMPLE 319 4-(4~{2-[4-(Benzothiazol-2-yloxy)-pheny[]-ethyl}-piperazine-1-carbonyi)-benzoic acid.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using terephthalic acid monomethyl ester and EXAMPLE 250, step 20 D. MS (ESI): exact mass calculated for C27H25N3O4S, 487.2; m/z found, 488.4 [M+Hf. 1H NMR (400 MHz, DMSO-c/6): 8.00 (d, J = 8.3, 2H), 7.93 (dd, J = 8.0, 0.8, 1H), 7.69 (dd, J = 8.0, 0.4, 1H), 7.50 (d, J = 8.3, 2H), 7.43 (dt, J = 7.5, 1.3, 1H), 7.40-7.29 (m, 5H), 3.66 (br s, 2H), 3.30 (br s, 2H), 2.88 (dd, J = 7.0, 7.0, 2H), 2.60 (dd, J = 8.3, 8.3, 2H), 2,55 (br s, 2H), 2.44 (br s, 2H).
O 206 544938 EXAMPLE 320 & MGyO o (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-pyridin-4-yl-rnethanone.
The title compound was prepared according to the procedure for EXAMPLE 317 using isonicotinic acid. MS (ESI): exact mass calculated for C25H24N4O2S, 444.2; m/z found, 445.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 8.74 (dd, J = 4.4, 1.6, 1H), 7.77 (dd, J = 8.1, 0.5, 1H), 7.71 (dd, J = 7.9, 0.8, 1H), 7.43 (dt, J = 10 7.4, 1.3, 1H), 7.45-7.39 (m, 2H), 7.35-7.28 (m, 7H), 3.87 (br s, 2H), 3.44 (br t, J = 3.9, 2H), 2.88 (dd, J = 10.1, 6.9, 2H), 2.71 (dd, J = 8.8, 5.5, 2H), 2.70-2.64 (m, 2H), 2.54-2.49 (m, 2H).
EXAMPLE 321 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yI)-(5-methyl-pyrazin-2-yl)-methanone.
The title compound was prepared according to the procedure for EXAMPLE 20 317 using 5-methyl-pyrazine-2-carboxyIic acid. MS (ESI): exact mass calculated for C25H25N5O2S, 444.2; m/z found, 445.4 [M+H]+. 1H NMR (400 MHz, CDCb): 8.89 (d, J =1.4, 1H), 8.45 (d, J =1.0, 1H), 7.76 (dd, J = 8.1, 0.5, 1H), 7.70 (dd, J = 8.0, 0.8, 1H), 7.43 (dt, J = 7.4, 1.3, 1H), 7.33-7.28 (m, 5H), 3.90 (brt, J- 4.7, 2H), 3.77 (brt, J~ 4.8, 2H), 2.92 (dd, J= 10.5, 6.5, 2H), 25 2.80-2.72 (m, 2H), 2.69-2.64 (m, 2H), 2.66 (s, 3H).
O 207 544938 EXAMPLE 322 sY° frN r\ ^ UyQ 0 (R)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-(tetrahydro-furan-2-yi)-methanone.
The titie compound was prepared according to the procedure for EXAMPLE 317 using 5-(R)-tetrahydro-furan-2-carboxyiic acid. MS (ESi); exact mass calculated for C24H27Ns03S, 437.2; m/z found, 438.5 [M+H]+. 1H NMR (400 MHz, CDCIs): 7.77 (d, J = 7.3, 1H), 7.71 (dd, J = 7.8, 0.8, 1H), 7.42 (dt, J = 7.3, 1.2, 1H), 7.33-7.26 (m, 5H), 4.65 (dd, J = 7.0, 5.3, 1H), 3.99 (ddd, J = 7,1, 6.7, 6.7, 1H), 3.92-3.86 (m, 1H), 3.82-3.72 (m, 2H), 3.76 (s, 1H), 3.70-3.58 (m, 2H), 2.90 (dd, J = 10.3, 7.3, 2H), 2.70 (dd, J = 8.6, 5.6, 2H), 2.64-2.54 (m, 3H), 2.38-2.28 (m, 1H), 2.14-1.90 (m, 4H).
EXAMPLE 323 O (S)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yI)-(tetrahydro-furan-2-yl)-methanone.
The title compound was prepared according to the procedure for EXAMPLE 317 using 5-(S)-tetrahydro-furan-2-carboxylic acid. MS (ESI): exact mass calculated for C24H27N3O3S, 437.2; m/z found, 438.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (d, J = 7.3, 1H), 7.71 (dd, J = 7.8, 0.8, 1H), 7.42 (dt, J = 7.3, 1.2, 1H), 7.33-7.26 (m, 5H), 4.65 (dd, J = 7.0, 5.3, 1H), 3.99 (ddd, J = 7.1, 25 6.7, 6.7, 1H), 3.89 (ddd, J = 7.7, 7.5, 5.8, 1H), 3,82-3.72 (mf 2H), 3.76 (s, 1H), / 208 544938 3.70-3.58 (m, 2H), 2.90 (dd, J = 10.3, 7.3, 2H), 2.70 (dd, J = 8.6, 5.6, 2H), 2.64-2.54 (m, 3H), 2.38-2.28 (m, 1H), 2.14-1.90 (m, 4H).
EXAMPLE 324 (4-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyi}-piperaz!n-1-yl}-(tetrahydro-furan-3-yl)-methanone, The title compound was prepared according to the procedure for EXAMPLE 10 317 using 5-tetrahydro-furan-3-carboxylic acid. MS (ESI): exact mass calculated for C24H27N3O3S, 437.2; m/z found, 438.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.1, 0.5, 1H), 7.71 (dd, J = 7.9, 0.8, 1H), 7.42 (dt, J = 7.5, 1.3, 1H), 7.33-7.26 (m, 5H), 4.06 (t, J-8.2, 1H), 3.97-3.87 (m, 3H), 3.77-3.67 (m, 2H), 3.59 (t, J = 5.1, 1H), 3.35-3.24 (m, 1H), 2.88 (dd, J = 10.2, 15 7.3, 2H), 2.79 (dd, J = 8.5, 5.7, 2H), 2.60-2.50 (m, 4H), 2.29 (dddd, J = 12.6, 7.6, 6.4, 6.4, 1H), 2.17-2.08 (m, 1H).
EXAMPLE 325 o l-(4-{2-[4-(BenzothiazoI-2-yloxy)-phenyI]-ethyl}-piperazin-1-yl)-2-hydroXy-ethanone.
The title compound was prepared according to the procedure for EXAMPLE 317 using gylcolic acid. MS (ESI): exact mass calculated for C21H23N3O3S, 397.2; m/z found, 398.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.1, 0.5, 1H), 7.71 (dd, J = 8.0, 0.7, 1H), 7.43 (dt, J = 7.5, 1.3, 1H), 7.35-7.28 (m, O 209 544338 5H), 4.21 (s, 2H), 3.75 (t, J = 5.0, 2H), 3.68 (br s, 1H), 3.35 (t, J = 5.0, 2H), 2.88 (dd, J = 10.1, 7.0, 2H), 2.70 (dd, J = 8.6, 5.6, 2H), 2.58 (ddd, J = 8,4, 8.3, 5.2, 1H).
EXAMPLE 326 2-[2-(4-{2-[4-(BenzothiazoI-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-oxo-ethylJ-cyclopentanone.
The titie compound was prepared according to the procedure for EXAMPLE 317 using 5- (2-oxo-cyclopentyl)-acetic acid. MS (ESI): exact mass calculated for C26H29N3O3S, 463.2; m/z found, 464.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.77 (d, J = 7.7, 1H), 7.71 (dd, J = 7.9, 0.7, 1H), 7.42 (dt, J = 7.5, 1.2, 1H), 7.33-7.28 (m, 5H), 3.80-3.64 (m, 2H), 3.54 (dd, J = 9.2, 3.9, 1H), 2.92-2.84 (m, 15 3H), 2.88 (dd, J= 10.1, 7.0, 2H), 2.68 (dd, J- 8.5, 5.6, 2H), 2.60-2.25 (m, 2H), 2.15-2.06 (m, 1H), 1.93-1.80 (m, 1H), 1.78-1.64 (m, 2H).
EXAMPLE 327 ^ 3-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1 -y!)-propionic acid trifluoromethansufonate salt.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using 3-piperazin-1-yl-propionic acid. MS (ESI): exact mass 25 calculated for C2iH23N303Si, 411.2; m/z found, 412.4 [M+H]\ 1H NMR (400 MHz, CDCI3): 11.25 (br s, 1H), 7.76 (dd, J = 8.0, 0.5, 1H), 7.69 (dd, J = 7.8, 0.6, 1H), 7.42 (dt, J = 7.4, 1.2, 1H), 7.35-7.28 (m, 5H), 3.76 (s, 1H), 3.04 (t, J = 210 544938 6.4, 4H), 2.91 (dd, J= 10.3, 5.4, 4H), 2.86-2.79 (m, 2H), 2.63 (t, J = 6.4, 1H)( 2.08 (s, 4H).
EXAMPLE 328 3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-piperidin-4~yl)-oxazo]idin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using 3-piperidin-4-yl-oxazolidin-2-one hydrochloride salt and 10 EXAMPLE 259, step A. MS (ESI): exact mass calculated for CaaHasNsOsSi, 423.2; m/z found, 424.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.1, 0.5, 1H), 7.69 (dd, J = 7.9, 1.1, 1H), 7.41 (dt, J = 8.5, 1.2, 1H), 7.35-7.28 (m, 5H), 4.36, (t, J = 7.8, 2H), 3.72 (t, J = 4.8, 2H), 3.86-3.76 (m, 1H), 3.57 (t, J = 8.1, 2H), 3.11 (brd, J = 11.8, 2H), 2.86 (dd, J- 11.0, 7.6, 2H), 2.66 (dd, J = 15 8.6, 5.2, 2H), 2.18 (dt, J = 11.7, 2.7, 2H), 1.89-1.72 (m, 4H).
EXAMPLE 329 4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl3-ethyl}-piperidin-4-y])-morpholin-3-one.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using piperidin-4-yl-morpholin-3-one and EXAMPLE 260, step A. MS (ESI); exact mass calculated for Ca^zNaOsSi, 437.2; m/z found, 438,4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.76 (d, J = 8.0, 1H), 7.70 (dd, J = 7.9, 25 0.7, 1H), 7.42 (dt, J = 7.4, 1.2, 1H), 7.33-7.28 (m, 5H), 4.57 (tt, J = 11.9, 4.3, 1H), 4.23 (s, 2H), 3.91, (t, J = 4.9, 2H), 3.34 (t, J = 5.1, 2H), 3.12 (for d, J = 211 544938 11.6, 2H), 2.87 (dd, J = 10.9, 7.6, 2H), 2.67 (dd, J = 8.7, 5.2, 2H), 2.23 (ddd, J = 11.7, 11.6, 2.5, 2H), 1.82 (ddd, J = 24.1, 12.1,3.8, 2H), 1.76-1.70 (m, 2H).
EXAMPLE 330 r-° ff ^ J o 4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyI}-piperidin-4-yl)-morpholin-3-orie.
The title compound was prepared according to the procedure for EXAMPLE 10 17, step A using piperidin-4-yl-morphoIin-3-one and EXAMPLE 260, step A. MS (ESI): exact mass calculated for C24H27N3O4S1, 453.2; m/z found, 454.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.76 (dd, J = 8.1, 0.5, 1H), 7.68 (dd, J = 7.9, 0.7, 1H), 7.40 (dt, J = 7.4, 1.3, 1H), 7.31-7.28 (m, 3H), 7.02-6.96 (m, 2H), 4.57 (tt, J = 12.1, 4.2, 1H), 4.22 (s, 2H), 4.14 (t, J = 5.6, 2H), 3.90 (t, J = 5.0, 15 2H), 3.33 (t, J = 5.1, 2H), 3.12 (br d, J = 11.7, 2H), 2.87 (t, J = 5.7, 2H), 2.32 (ddd, J= 11.8, 11.8, 2.4, 2H), 1.82 (dddd, J = 12.2, 12.1, 12.1, 3.8, 2H), 1.75-1.68 (m, 2H).
EXAMPLE 331 3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-oxazolidin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 17, step A using 3-piperidln-4-yl-oxazolidin-2-one hydrochloride salt and EXAMPLE 259, step A. MS (ESI): exact mass calculated for C23H25N3O4S1, 439.2; m/z found, 440.5 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.76 (dd, J = 8.1, 0.7, 1H), 7.69 (dd, J = 8.0, 0.7, 1H), 7.42 (dt, J = 8.6, 1.3, 1H), 7.35-7.26 (m, 212 544938 3H), 7.02-6.97 (m, 2H), 4.36 (dd, J = 8.7, 7.3, 2H), 4.14 (t, J = 5.7, 2H), 3.80 (ddd, J= 16.4, 11.0, 5.6, 1H), 3.60-3.53 (m, 2H), 3.12 (brd, J= 12.0, 2H), 2.87 (d, J - 5.7, 2H), 2.28 (ddd, J = 11.7, 11.6, 3.8, 2H), 1.90-1.74(m, 4H).
EXAMPLE 332 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4~carboxylic acid benzyloxy-amide.
A solution of 1 -{2-[4-(benzothiazol-2-yloxy)-phenyI]-ethyI}-piperidine-4- carboxylic acid EXAMPLE 34, step A (383 mg, 1.0 mmol) in CH2CI2 (10 mL) was treated with N-methyimorpholine (0.24 ml, 2.2 mmol) and cyanuric chloride (61 mg, 0.3 mmol) and the resulting solution stirred for 1 h, at which time the reaction was treated with O-benzyl hydroxylamine and stirred for 16h. The 15 reaction was filtered through diatomaceous earth concentrated and purified on Si02 (12 g, 0-10% 2M NH3/MeOH/CH2Cl2) to give the title compound (81 mg,17% yield). MS (ESI): exact mass calculated for C28H29N3O3S1, 487.2; m/z found, 488.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 8.34 (br s, 1H), 7.76 (dd, J = 8.1, 0.5, 1H), 7.70 (dd, J = 7.9, 0.7, 1H), 7.45-7.39 (m, 6H), 7.34-7.28 (m, 4H), 20 4.96 (br s, 2H), 3.05 (br d, J = 11.6, 2H), 2.85 (dd, J = 10.6, 7.6, 2H), 2.63 (dd, J = 8.5, 5.5, 2H), 2.04 (ddd, J= 11.0, 11.0, 2.8, 2H), 1.91-1.76 (m, 2H).
EXAMPLE 333 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-acetic acid.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using piperidin-4-yi-acetic acid ethyl ester and EXAMPLE 250, step 213 544938 D. MS (ESI): exact mass calculated for C22H24N203Si, 396.2; m/z found, 397.4 [M+Hf. 1H NMR (400 MHz, CD3OD): 8.34 (brs, 1H), 7.82 (dd, J= 7.9, 0.6, 1H), 7.67 (dd, J = 8.1, 0.5, 1H), 7.53-7.33 (m, 6H), 3.78-3.66 (m, 2H), 3.46-3.38 (m, 2H), 3.22-3.14 (m, 2H), 3.14-3.07 (m, 2H), 2.39 (br d, J = 6.1, 5 1H), 2.20-2.08 (br s , 1H), 2.11 (br d, J = 13.5, 1H), 1.72-1.54 (m, 2H).
EXAMPLE 334 (R)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-piperidin-4-yi)-4-hydroxy-10 pyrrolidin-2-one The title compound was prepared according to the procedure for EXAMPLE 262, step A using (R)-4-hydroxy-1 -piperidin-4-yl-pyrrolidin-2-one acetic acid salt and EXAMPLE 261, step A. MS (ESi): exact mass calculated for 15 C24H27N3O3S1, 437.2; m/z found, 438.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.1, 0.5, 1H), 7.66 (dd, J = 7.9, 0.7, 1H), 7.40 (dt, J = 7.7, 1.3, 1H), 7.28-7.24 (m, 5H), 4.52 (ddd, J = 8.5, 5.9, 2.4, 1H), 4.11-4.00 (m, 1H), 3.60 (dd, J = 10.7, 5.6, 1H), 3.31 (dd, J = 10.7, 2.2, 1H), 3.12-3.04 (m, ^H), 2.83 (dd, J = 9.7, 6.5, 2H), 2.72 (dd, J = 17.2, 6.6, 1H), 2.63 (dd, J = 9.8, 6.4, 20 2H), 2.72 (dd, J= 17.2,2.6, 1H), 2.21-2.12 (m, 2H), 1.85-1.67 (m, 4H).
EXAMPLE 335 O 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid 25 hydroxyamide 214 544938 The title compound was prepared according to the procedure for EXAMPLE 262, step A using piperidine-4-carboxylic acid hydroxyamide, MS (ESI): exact mass calculated for C2iH23N3C>3Si, 397.2; m/z found, 398.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73-7.60 (m, 2H), 7.40-7.30 (m, 1H), 7.30-7.16 (m, 5H), 5 3.48-3.36 (br s, 2H), 3.10-2.95 (m, 4H), 2.80-2.50 (br m, 3H), 2.23-1.96 (br m, 5H).
EXAMPLE 336 (S)-1 -(1-{2-[4-(Benzothiazol-2-yloxy)-pheny]]-ethyl}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using (S)-4-hydroxy-1-piperidin-4-yl-pyrroiidin-2-one acetic acid 15 salt, EXAMPLE 261, step A using (S)-4-bromo-3-hydroxybutyrate . MS (ESi): exact mass calculated for C24H27N303Si, 437.2; m/z found, 438.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.77 (dd, J = 8.1, 0.5, 1H), 7.66 (dd, J = 7.9, 0.7, 1H), 7.40 (dt, J = 7.7, 1.3, 1H), 7.28-7.24 (m, 5H), 4.52 (ddd, J = 8.5, 5.9, 2.4, 1H), 4.11-4.00 (m, 1H), 3.60 (dd, J = 10.7, 5.6, 1H), 3.31 (dd, J= 10.7, 2.2, 1H), 20 3.12-3.04 (m, 2H), 2.83 (dd, J = 9.7, 6.5, 2H), 2.72 (dd, J= 17.2, 6.6, 1H), 2.63 (dd, J = 9.8, 6.4, 2H), 2.72 (dd, J = 17.2, 2.6, 1H), 2.21-2.12 (m, 2H), 1.85-1.67 (m, 4H).
EXAMPLE 337 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyi}-piperidin-4-yl)-carbamic acid tert-butyl ester. 215 544938 The title compound was prepared according to the procedure for EXAMPLE 262, step A using piperidin-4-yl-carbamic acid tert-butyl ester. MS (ESI): exact mass calculated for C25H31N3O3S1, 453,2; m/z found, 454.4 [M+Hf. 1H NMR 5 (400 MHz, CDCI3): 7.73 (dd, J = 8.2, 0.6, 1H), 7.65 (dd, J = 7.9, 0,7, 1H), 7.39 (dt, J = 7.4, 1.3, 1H), 7.29-7.23 (m, 5H), 4.47 (br d, J = 6.6, 1H), 3.55-3.45 (m, 1H), 2.93 (br d, J = 11.3, 2H), 2.82 (dd, J = 11.0, 7.7, 2H), 2.60 (dd, J = 8.6, 5.3, 2H), 2.16 (t, J = 11.3, 2H), 1.97 (br d, J = 11.1, 2H), 1.45 (s, 9H).
EXAMPLE 338 2-{4-[2-(4-Pluoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazoIe.
The title compound was prepared according to the procedure for EXAMPLE 15 262, step A using 4-ffuoro piperidine. MS (ESi): exact mass calculated for C20H21F1N3O1S1, 356.1; m/z found, 357.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (dd, J = 8.1, 0.5, 1H), 7.65 (dd, J = 8.0, 0.7, 1H), 7.41-7.36 (m, 1H), 7.28-7.24 (m, 5H), 4.70 (dm, J = 48.6, 1H), 2.85 (dd, J = 10.9, 7.7, 2H), 2.71-2.63 (m, 2H), 2.62 (dd, J = 8.3, 5.4, 2H), 2.52-2.44 (m, 2H), 2.03-1.86 (m, 2-{4~[2-{4,4-Difluoro-piperidin-1-yl)-ethyi]-phenoxy}-benzothiazole.
The titie compound was prepared according to the procedure for EXAMPLE! 262, step A using 4,4-difluoro piperidine. MS (ESi): exact mass calculated for C20H20F2N3O1S1, 374.1; m/z found, 375.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (dd, J = 8.1, 0.6, 1H), 7.65 (dd, J = 8.0, 0.7, 1H), 7.41-7.36 (m, 1H), 7.28- EXAMPLE 339 216 544938 7.24 (m, 5H), 2.82 {dd, J = 10.2, 6.4, 2H), 2.71-2.60 (m, 6H), 2.09-1.97 (m, 4H).
EXAMPLE 340 (f?)-1-{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyI}-pyrrolidin-3-oi.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using (f?)-3-hydroxypyrrolidine. MS (ESI): exact mass calculated 10 for C19H2oN202Si, 340.1; m/z found, 341.1 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (dd, J = 8.0, 0.4, 1H), 7.66 (dd, J = 7.9, 0.8, 1H), 7.39 (dt, J = 7.4, 1.2, 1H), 7.31-7.24 (m, 5H), 4.36 {dddd, J = 7.3, 4.8, 2.2, 2.2, 1H), 2.96 (ddd, J = 8.5, 8.5, 5.1, 1H), 2.90-2.83 (m, 2H), 2.79-2.70 {m, 3H), 2.58 (dd, J = 10.0, 5.2, 2H), 2.36 (ddd, J = 8.8, 8.8, 6.5, 1H), 2.21 (dddd, J = 13.7, 8.6, 7.2, 5.1, 1H), 15 1.82-1.73 (m, 1H).
EXAMPLE 341 N-(1-{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyI}-piperidin-4-ylHormamide.
The title compound was prepared from EXAMPLE 337 following the procedure for EXAMPLE 266, step B and EXAMPLE 317. MS (ESi): exact mass calculated for Cs^NaOsS^ 381.2; m/z found, 382.4 [M+Hf. 1H NMR (400 MHz, CDCh): 8.16 (s, 1H), 7.72 (d, J = 8.6, 1H), 7.65 (dd, J = 7.9, 0.7, 1H), 25 7.42-7.36 (m, 1H), 7.31-7.23 (m, 5H), 4.03-3.93 (m, 1H), 3.13-3.03 (m, 2H), 2.90 (dd, J = 11.1, 7.2, 2H), 2.75-2.69 (m, 2H), 2.34 (t, J - 9.2, 2H), 2.08-2.00 (m, 2H), 1.72-1.60 (m, 2H). 217 544938 EXAMPLE 342 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-piperidin-4-yl)-urea 1-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyi}-piperidin-4-yIamine hydrochloride was prepared from (1-{2~[4-(benzothiazol-2-yIoxy)-phenyi]-ethyl}-piperidin-4-yl)~ carbamic acid tert-butyi ester EXAMPLE 337 following the procedure for EXAMPLE 266, step B. The resulting amine hydrochloride (227 mg, 0.58 mmol) in CH2CI2 (5 mL) was treated with pyridine (0.14 mL, 1.7 mmol), 10 trimethylisocyanate (0.09 ml, 0.64 mmol), and triethylamine (0.08 mL, 0.58 mmol) and the reaction stirred for 16h. The reaction was diluted with CH2CI2 (25 mL) and washed with NaHC03 (30 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The crude material was purified on SiC>2 (12 g, 0-10% [2 M NH3] CH3OH/CH2CI2) to give 15 the title compound (134 mg, 58% yield). MS (ESI): exact mass calculated for C21H24N4O2S1, 396.2; m/z found, 397.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J- 8.7, 1H), 7.65 (dd, J = 7.9, 0.7, 1H), 7.42-7.36 (m, 1H), 7.31-7.23 (m, 5H), 4.93 (d, J = 8.0, 1H), 4.78 (s, 2H), 3.93 (br d, J = 11.7, 1H), 2.82 (dd, J = 10.7, 7.6, 2H), 2.60 (dd, J = 8.5, 5.4, 2H), 2.16 (t, J = 11.3, 2H), 1.97 /dd, J = 20 12.7, 3.1, 2H), 1.47 (dddd, J = 12.8, 12.6, 12.6, 3.7, 2H).
EXAMPLE 343 H 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyi}-piperidin-4-yI)-3-cyano-2-25 phenyl-isourea 218 544938 The 1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethy!}-piperidin-4-yiamirie hydrochloride was prepared from (1-{2-[4-(benzothiazol-2-yIoxy)-phenyl]-ethyi}-piperidin-4-yl)-carbamic acid tert-butyl ester EXAMPLE 337 by removal of the Boc group according to EXAMPLE 266, step B. The free base was prepared 5 by suspending 1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ylamine hydrochloride (1.3 g, 3.3 mmol) in CH2CI2 (20 mL) and washing with a solution of saturated NaHC03 (20 mL). The organic layer was dried over Na2S04l filtered and concentrated under reduced pressure to give 1.0 g (83% yield) of 1 -{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ylamine free base. A 10 solution of 1-{2-[4-(benzothiazol-2-yloxy)-phenyI]-ethyl}-piperidin-4-yl amine (145 mg, 0.4 mmol) in ethanol (5 mL) was treated with diphenyl cyanocarbodiimidate (319 mg. 1.34 mmol) and heated to 80 °C for 16h. The reaction was concentrated under reduced pressure and purified on Si02 (12 g, 0-10% [2 M NH3 CH3OH]/CH2CI2) to give of the title compound (173 mg, 85% 15 yield). MS (ESI): exact mass calculated for C28H27N502Si, 496.2; m/z found, 498.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J = 8.7, 1H), 7.66 (dd, J = 7.9, 0.7, 1H), 7.45-7.36 (m, 4H), 7.31-7.24 (m, 5H), 7.08 (d, J = 7.8, 2H), 6.36 (br d,J- 6.5, 1H), 3.87-3,76 (m, 1H), 3.02 (br d, J= 11.2, 2H), 2.83 (dd, J = 8.4, 7.3, 2H), 2.64 (dd, J = 8.6, 5.4, 2H), 2.21 (t, J = 11.1, 2H), 2.07 (d, J = 20 11.0, 2H), 1.76 (dd, J = 20.7, 10.4, 2H).
EXAMPLE 344 h 1-(1-{2~[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-25 methyl-isothiourea.
The 1-{2-[4-{benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidin-4-ylamine hydrochloride was prepared from (1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-carbamic acid tert-butyl ester EXAMPLE 337 by removal of the 30 Boc group according to EXAMPLE 266, step B. The free base was prepared 219 544938 WO 2005/012297 PCT/US2004/024309 according to EXAMPLE 343. A solution of 1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl amine (145 mg, 0.4 mmol) in ethanol (5 mL) was treated with dimethyl-N-cyanodithioiminocarbonate (180 mg. 1.34 mmol) and heated to 80 °C for 16h, The reaction was concentrated under reduced 5 pressure and purified on Si02 (12 g, 0-10% 2M NH3/CH3OH/CH2CI2) to give of the title compound (143 mg, 69% yield). MS (ESi): exact mass calculated for C23H25N5OiS2) 451.2; m/z found, 452.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (dd,J = 8.1, 0.5, 1H), 7.66 (dd, J= 7.9, 0.7, 1H), 7.41-7.36 (m, 2H), 7.29-7.24 (m, 5H), 6.13 (br d, J = 196, 2H), 2.97 (br d, J = 12.0, 2H), 2.82 (dd, J = 10 10.3, 7.3, 2H), 2.62 (dd, J= 8.5, 5.5, 2H), 2.60-2.44 (brs, 3H), 2.18 (t, J= 11.5, 2H), 2.03 (d, J = 13.5, 2H), 1.7-1.55 (m, 2H).
EXAMPLE 345 H N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]~ethyl}-piperidin-4-yI)-methanesulfonamide.
The 1-{2-[4-(benzothiazol-2-yloxy)-phenyI]-ethy!}-piperidin-4-yiamine hydrochloride was prepared from (1-{2-[4-(benzothiazol-2-yloxy)-phenylJ-ethyl}-20 piperidin-4-yl)-carbamic acid tert-butyl ester EXAMPLE 337 by removal of the Boc group according to EXAMPLE 266, step B. The free base was prepared according to EXAMPLE 343. The free base (240 mg, 0.68 mmol) in CH2CI2 (7 mL) was treated with triethylamine (142 jjL, 1.0 mmol) followed by methanesulfonyl chloride (77 pL, 1.0 mmol) and the solution stirred for 16 h. 25 The reaction was diluted with CH2CI2 (20 mL) and washed NaHCOs solution (30 mL). The organic layer was dried and concentrated under reduced pressure then purified on Si02 (12 g, 0-10% 2M NH3/MeOH : CH2CI2) to give 168 mg (57% yield) of the title compound. MS (ESi): exact mass calculated for CsiHssNaOaSs, 431.1; m/z found, 432.3 [M+Hf, 1H NMR (400 MHz, CDCI3): 30 7.73 (d, J = 8.0, 1H), 7.65 (dd, J = 7.9, 0.7, 1H), 7.42-7,36 (m, 1H), 7.29-7.24 220 544938 (m, 5H), 4.45 (d, J = 7.6, 1H), 3.42-3.31 (m, 1H), 2.99 (s, 3H), 2.93 (br d, J = 12.0, 2H), 2.81 (dd, J = 10.6, 7.5, 2H), 2.60 (dd, J- 8.5, 5.4, 2H), 2.18 (t, J = 11.0, 2H), 2.02 (d, J= 12.5, 2H), 1.47 (dddd, J = 11.2, 11.1, 11.1, 3.7, 2H).
EXAMPLE 346 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-piperidin-4-yl)-3-cyano-2-methyl-guanidine.
A solution of 1-(1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-3-cyano-2-phenyl-isourea, EXAMPLE 343, (76 mg, 0.15 mmo!) in ethanol (3 mL) was treated with a solution of 40% methylamine in water (0.2 ml) and the solution stirred at 80 °C for 1 h. The reaction was cooled to 23 °C and concentrated under reduced pressure to give a crude solid that was purified on 15 Si02 (4 g, 0-10% 2M NH3/MeOH : CH2CI2) to give 50 mg (76% yield) of the title compound. MS (ESI): exact mass calculated for C23H26N6O1S1, 434.2; m/z found, 435.4 [M+H]+. 1H NMR (400 MHz, CDGI3): 7.72 (d, J-8.1, 1H), 7.67 (dd, J = 7.9, 0.7, 1H), 7.42-7.36 (m, 2H), 7.29-7.24 (m, 5H), 5.67 (br s, 1^H), 4.75 (br s, 1H), 3.63 (br s, 1H), 2.94 (br d, J = 11.9, 2H), 2.86 (d, J = 4.9, 2H), 20 2.82 (dd, J = 10.4, 7.4, 2H), 2.61 (dd, J = 8.5, 5.5, 2H), 2.18 (t, J = 11.4, 2H), 2.05-1.96 (m, 2H), 2.61 (dddd, J~ 12.3, 12.3, 12.3, 3.6, 2H).
EXAMPLE 347 H 8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-1 -phenyi-1,3,8-triaza-spiro[4.5]decan-4-one.
H H 221 544938 The title compound was prepared according to the procedure for EXAMPLE 262, step A using 1-phenyl~1,3,8-triaza-spiro[4.5]decan-4-one. MS (ESI): exact mass calculated for C28H28N4O2S1, 484.2; m/z found, 485.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.74 (dd, J = 8.G, 0.5, 1H), 7.66 (dd, J=7.9, 0.7, 1H), 5 7.52 (s, 1H), 7.42-7.36 (m, 1H), 7.34-7.24 (m, 6H), 6.91 (d, J= 8.0, 1H), 6.87 (t, J = 7.3, 1H), 4.75 (s, 2H), 2.95-2.85 (m, 4H), 2.76-2.66 (m, 4H), 1.76 (d, J = 13.9, 2H).
EXAMPLE 348 8-{2-[4-( Benzoth iazol-2-yloxy)-pheny l]-ethyi}-1,3,8-triaza-sp i ro [4.5]deca ne-2,4-dione.
The title compound was prepared according to the procedure for EXAMPLE 15 262, step A using 1,3,8-triaza-spiro[4.5]decane-2,4-dione. MS (ESI): exact mass calculated for C22H22N4O3S1, 422.1; m/z found, 423.4 [M+Hf, 1H NMR (400 MHz, CDCI3): 7.73 (dd, J = 8.1, 0.5, 1H), 7.67 (dd, J= 7.9, 1.1, 1H), 7.42-7.36 (m, 1H), 7.34-7.24 (m, 5H), 3.0 (ddd, J = 9.2, 4.3, 4.3, 2H), 2.86 (dfJ, J = 10.6, 6.9, 2H), 2.69 (dd, J = 9.0, 5.3, 2H), 2.72 (t, J = 10.2, 2H), 2.19-2.10 (m, 20 2H), 1.75 (d, J= 13.6, 2H).
EXAMPLE 349 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-carbamic 25 acid tert-butyl ester. 222 544938 The titie compound was prepared according to the procedure for EXAMPLE 262, step A using methyl-piperidin-4-yi-carbamic acid tert-butyl ester. MS (ESI): exact mass calculated for C26H23N3O3S1, 467,2; m/z found, 468.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (dd, J = 8.1, 0.5, 1H), 7.66 (dd, J = 5 7.9, 0.7, 1H), 7.41-7.36 (m, 1H), 7.29-7.25 (m, 5H), 4.10-3.95 (brm, 1H), 3.07 (d, J = 11.6, 2H), 2.83 (dd, J = 11.1, 7.8, 2H), 2.75 (s, 3H), 2.61 (d, J = 8.6, 5.2, 2H), 2.11 (W=10.9, 2H), 2.19-2.10 (m, 2H), 1.77 (dddd, J = 12.1, 12.0, 12.0, 3.3, 2H), 1.70-1.64 (m, 2H), 1.47 (s, 9H).
EXAMPLE 350 N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyf}-piperidin-4-yl)-N-methyl-acetamide.
The title compound was prepared from EXAMPLE 349 following EXAMPLE 266, step B, EXAMPLE 343 and EXAMPLE 345 using acetyl chloride. MS (ESI): exact mass calculated for C23H27N3O2S1, 409.2; m/z found, 410.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (dd, J = 8.1, 0.6, 1H), 7.66 (dd, J = 8.0, 1.1, 1H), 7.41-7.36 (m, 1H), 7.31-7.25 (m, 5H), 4.53 (tt, J= 12.0, 4.2, 20 0.5H), 3.54 (tt, J = 11.7, 4.0, 0.5H), 3.15-3.04 (m, 2H), 2.90-2.78 (m, 5H), 2.70-2.58 (m, 2H), 2.24-2.06 (m, 5H), 2.00-1.96 (m, 1H), 1.82-1.60 (m, 3H).
EXAMPLE 351 N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl3-ethyl}-piperidin-4-yl)-N-methyl-methanesulfonamide. 223 544938 The title compound was prepared from EXAMPLE 349 following EXAMPLE 266, step B, EXAMPLE 343 and EXAMPLE 345 using methanesulfonyl chloride. MS (ESI): exact mass calculated for C25H29N3O4S, 467.2; m/z found, 468.4 [M+Hf. 1H NMR (400 MHz, CDCb): 7.73 (d, J = 8.1, 1H), 7.66 (dd, J = 5 7.9, 0.7, 1H), 7.42-7.36 (m, 1H), 7.29-7.24 (m, 5H), 3.78 (tt, J~ 11.9, 4.2, 1H), 3.08 (dd, J= 9.6, 2.1, 1H), 2.84 (s, 3H), 2.82 (s, 3H), 2.83-2.79 (m, 2H)S 2.61 (dd, J- 8.5, 5.3, 2H), 2.18 (ddd, J = 11.8, 11.8, 2.2, 2H), 1.86 (dddd, J= 12.2, 12.0, 12.0, 3.4, 2H), 1.76-1.69 (m, 2H).
EXAMPLE 352 O Acetic acid [(1 -{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-carbamoyl]-methyl ester.
The title compound was prepared from EXAMPLE 349 following EXAMPLE 266, step B, EXAMPLE 343 and EXAMPLE 345 using acetic acid chlorocarbonylmethyl ester. MS (ESI): exact mass calculated for C23H27N3O2S1, 467.2; m/z found, 468.4 [M+Hf. 1H NMR (400 MHz, CC/CI3): 7.73 (dd, J = 8.1, 0.5, 1H), 7.66 (d, J = 7.9, 1H), 7.42-7.36 (m, 1H), 7.29-7.24 20 (m, 5H), 4.76 (s, 0.6H), 4.71 (s, 1.4H), 4.48 (tt, J = 12.0, 4.3, 0.7 H), 3.36 (tt, J = 11.6, 4.4, 0.3 H), 3.16-3.04 (m, 2H), 2.90-2.78 (m, 5H), 2.68-2.58 (m, 2H), 2.19 (s, 3H), 2.19-2.05 (m, 2H), 2.01-1.84 (m, 1H), 1.82-1.60 (m, 3H).
EXAMPLE 353 N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]~ethyl}-piperidin-4-yj)-N-acetamide, H 224 544938 The title compound was prepared from EXAMPLE 337 following EXAMPLE 266, step B, EXAMPLE 343 and EXAMPLE 345 using acetyl chloride. MS (ESI): exact mass calculated for Czs^siNaCUS, 395.2; m/z found, 396,3 5 [M+Hf. 1H NMR (400 MHz, CDCIg): 7.73 (d, J = 8.0, 1H), 7.66 (dd, J = 7.9, 0.6, 1H), 7.42-7.36 (m, 1H), 7.29-7.24 (m, 5H), 5.48 (d, J= 7.8, 1H), 3.87-3.77 (m 1H), 2.95 (dd, J = 11.6, 2H), 2.83 (dd, J= 10.8, 7.6, 2H), 2.62 (dd, J = 8.5, 5.3, 2H), 2.18 (d, J = 11.4, 2H), 2.00-1.94 (m, 2H), 1.98 (m, 2H), 1.49 (dddd, J = 12.3,12.2, 12.2, 3.6, 2H).
EXAMPLE 354 Acetic acid (1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ylcarbamoyl)-methyl ester.
The titie compound was prepared from EXAMPLE 337 according to EXAMPLE 266, step B, EXAMPLE 343 and EXAMPLE 354 using acetic acid chlorocarbonylmethyl ester. MS (ESI): exact mass calculated for j C24H27N3O4S, 453.2; m/z found, 454.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 20 7.73 (dd, J = 8.2, 0.6, 1H), 7.67 (dd, J = 7.9, 0.7, 1H), 7.42-7.36 (m, 1H), 7.29-7.24 (m, 5H), 6.05 (df J = 8.0, 1H), 4.54 (s, 2H), 3.96-3.85 (m 1H), 3.00 (d, J = 8.2, 0.6, 2H), 2.85 (dd, J = 10.6, 7,4, 2H), 2.85 (dd, J = 10.6, 7.4, 2H), 2.66 (dd, J = 8.6, 5.3, 2H), 2.23 (t, J = 11.4, 2H), 2.18 (s, 3H), 1.98 (d, J = 9.7, 2H), 1.57 (dddd, J= 12.4, 12.4, 12.3, 3.6, 2H).
EXAMPLE 355 225 544938 (S)-2-{{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-methyl-amino)-3-(1H-imidazol-2-yl)-propionic acid.
The title compound was prepared according to the procedure for EXAMPLE 5 262, step A using (S)-3-{1 H-imidazol-2-yi)-2-methylamino-propionic acid, MS (ESI): exact mass calculated for C22H22N4O3S1, 422.1; m/z found, 423.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 8.85, (s, 1H), 7.81 (dd, J= 7.9, 0.6, 1H), 7.72 (dd, J- 8.1, 0.5, 1H), 7.58-7.42 (m, 4H), 7.39-7.34 (m, 3H), 4.34, (dd, J = 9.3, 4.9, 3H), 3.71-3.42, (m, 4H), 3.35-3.32 (m, 2H), 3.20 (d, J = 8.6, 2H), 3.08 10 (s, 3H).
EXAMPLE 356 2-(4-{2-[4-(3-Nitro-pyridin-2-yl)-[1,4]diazepan-1-yl]-ethyl}-phenoxy)-15 benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 262, step A using 1 -(3-nitro-pyridin-2-yl)-[1,4]diazepane. MS (ESI): exact mass calculated for C25H25N5O3S1, 475.2; m/z found, 476,1 [M+Hf. 1H^MMR 20 (400 MHz, CDCI3): 8.36 (dd, J = 4.5, 1.7, 1H), 8.14 (dd, J = 8.1, 1.7, 1H), 7.77 (dd, J = 8.1, 0.5, 1H), 7.70 (dd, J = 8.0, 0.7, 1H), 7.45-7.40 (m, 1H), 7.29-7,24 (m, 5H), 6.73 (dd, J = 8.0, 4.4, 1H), 3.80-3.75 (br s, 2H), 3.47-3.40 (br s, 2H), 3.07-3.01 (brs, 2H), 2.95-2.88 (m, 2H), 2.86-2.79 (m, 4H), 2.20-2.10 (brs, 2H) EXAMPLE 357 2-(4-Piperidin-1-ylmethyl-phenoxy)-benzothiazole, 226 544938 The titie compound was prepared according to the procedure for EXAMPLE 251, step B using piperidine. MS (ESi): mass calculated for C19H20N2OS, 324.4; m/z found, 325.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.75 (d, J = 8.2, 1H), 7.73 (d, J = 8.2, 1H), 7.36-7.42 (m, 3H), 7.24-7.32 (m, 3H), 3.49 (s, 2H), 5 2.39 (br s, 3H), 1.56-1.64 (m, 5H), 1.40-1.48 (m, 2H).
EXAMPLE 358 1-[4-(Benzothiazol-2-yloxy)-benzyl]-4-phenyl-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 251, step B using 4-phenyl-piperidin-4-ol. MS (ESI): mass calculated for C25H24N2O2S, 416.5; m/z found, 417.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.75 (d, J = 8.0, 1H), 7.66 (d, J = 8.0, 1H), 7.55-7.51 (m, 2H), 7.47-7.25 (m, 15 9H), 3.63 (s, 2H), 2.85-2.77 (m, 2H), 2.50 (dt, J= 11.8, 2.5, 2H), 2.18 (dt, J = 13.0, 4.4, 2H), 1.80-1.74 (m, 2H), 1.55 (br s, 1H).
EXAMPLE 359 / 1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ol.
The title compound was prepared according to the procedure for EXAMPLE 251, step B using 4-piperidinol. MS (ESI): mass calculated for CigH2oN202S, 340.4; m/z found, 341.3 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.74 (d, J = 8.0, 25 1H), 7.67 (d, J = 8.0, 1H), 7.42-7.36 (m, 3H), 7.32-7.24 (m, 3H), 3.68-3.64 (m, 1H), 3.46 (s, 2H), 2.81-2.25 (m, 2H), 2.20-2.15 (m, 2H), 1.95-1.90 (m, 2H), 1.67-1.58 (m, 3H). 227 544938 EXAMPLE 360 OH {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methanol, The title compound was prepared according to the procedure for EXAMPLE 251, step B using piperidin-4-yi-methanoi. MS (ESI): mass calculated for C20H22N2O2S, 354.5; m/z found, 355.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.67 (d, J = 8.0, 1H), 7.42-7.37 (m, 3H), 7.32-7.25 (m, 3H), 3.54 (s, 2H), 3.51 (d, J = 6.5, 2H), 2.97-2.90 (m, 2H), 2.01 (dt, J = 11.6, 10 2.4, 3H), 1.73 (d, J= 12.1, 2H), 1.58-1.47 (m, 1H), 1.37-1.26 (m, 2H).
EXAMPLE 361 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methanesuifonamide, The title compound was prepared according to the procedure for EXAMPLE 253, step A and B followed by EXAMPLE 258 step C, MS (ESI): mass/ calculated for C20H23N3O3S2, 417.6; m/z found, 418.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.68 (d, J = 8.0, 1H), 7.42-7.36 (m, 3H), 20 7.35-7.25 (m, 3H), 4.32-4.5 (m, 1H), 3.58 (s, 2H), 3.43-3.32 (m, 1H), 2.99 (s, 3H), 2.87-2.80 (m, 2H), 2.18-2.10 (m, 2H), 2.04-1.96 (m, 2H), 1.64-1.54 (m, 2H).
EXAMPLE 362 O 228 544938 N-{l-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyi}-2-hydroxy-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 5 258, step A and B followed by EXAMPLE 253 step C using giycolic acid. MS (ESI): mass calculated for C22H25N3O3S, 411.5; m/z found, 412.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.2, 1H), 7.67 (d, J = 8.2, 1H), 7.42-7.37 (m, 3H), 7.32-7.25 (m, 3H), 4.11 (s, 2H), 3.51 (s, 2H), 3.24 (t, J = 6.3, 2H), 2.88-2.94 (m, 2H), 2.20 (d, J = 11.5, 1H), 2.02-1.92 (m, 2H), 1.72-1.65 (mf 2H), 10 1.62-1.50 (m, 2H), 1.36-1.26 (m, 2H).
EXAMPLE 363 {1-[4-(BenzothiazoI-2-yloxy)-benzyl]-piperidin-4-yI}-carbamic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 253, step A and B followed by EXAMPLE 258 step C using methyl isocyanate. MS (ESI): mass calculated for C2iH23N303S3 397.5; m/z found, 398.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J= 8.0, 1H), 7.67 (d, J = 8.0, 1H), £.42-20 7.36 (m, 3H), 7.32-7.24 (m, 3H), 4.57 (brs, 1H), 3.66 (s, 3H), 3.51 (s, 2H), 2.85-2.79 (m, 2H), 2.18-2.09 (m, 2H), 1.98-1.90 (m, 2H), 1.51-1.40 (m, 2H).
EXAMPLE 364 {1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-urea.
The title compound was prepared according to the procedure for EXAMPLE 258, step A, B and C using trimethylsilyl isocyanate. MS (ESI): mass 229 H O 544938 calculated for Cz-^^OzS, 396.5; m/z found, 397.4 [M+Hf. 1H NMR (400 MHz, CDCIs): 7.74 (d, J= 8.0, 1H), 7.67 (d, 8.0, 1H), 7.42-7.36 (m, 3H), 7.32-7.24 (m, 3H), 4.64 (brs, 1H), 4.35 (s, 2H)t 3.50 (s, 2H), 3.07 (brt, J= 6.3, 2H), 2.94-2.88 (m, 2H), 1.86-2.01 (m, 2H), 1.72-1.66 (m, 2H), 1.56-1.44 (s, 5 1H), 1.24-1.23 (m, 2H).
EXAMPLE 365 N-{1-[4-(Benzothiazol-2-yIoxy)-benzyi]-piperidin-4-ylmethyl}-2,2J2-trifluoro-10 acetamide The titie compound was prepared according to the procedure for EXAMPLE 258, step A and B and EXAMPLE 257, step C using trifluoroacetic acid. MS (ESI): mass calculated for C22H22F3N302S, 449.5; m/z found, 450.4 [M+Hf. 15 1H NMR (400 MHz, CDCI3): 7.74 (d, J- 8.0, 1H), 7.67 (d, J- 8.0, 1H), 7.42-7.36 (m, 3H), 7.32-7.24 (m, 3H), 6.41 (br s, 1H), 3.51 (s, 2H), 3.28 (t, J = 6.46, 2H), 2.92 (d, J = 11.5, 2H), 2.02-1.94 (m, 2H), 1.74-1.54 (m, 3H), 1.38-1.27 (m, 2H).
/ EXAMPLE 366 {4-[4-(Benzothiazol-2-yloxy)-benzySJ-piperazin-1-yl}-acetic acid.
The title compound was prepared according to the procedure for EXAMPLE 25 259, step C and D and EXAMPLE 250, step D using piperazin-1-yl-acetic acid. MS (ESI): mass calculated for C2oH2iN303S, 383.5; m/z found, 384.4 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.77 (d, J = 8.0, 1H), 7.62 (d, J = 8.0, 1H), 7.50- o 230 WO 2005/012297 544938 PCT/US2004/024309 7.46 (m, 2H), 7.42-7.26 (m, 4H), 6.67 (s, 2H), 3.60 (s, 2H), 3.34 (brs, 4H), 2.77 (brs, 4H).
EXAMPLE 367 2-[4-(4-Methanesulfonyi-piperazin-1-ylmethyl)-phenoxy]-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 257, step A and B and EXAMPLE 258 step C. MS (ESI): mass calculated for 10 C19H2iN303S2, 403.53; m/z found, 404.3 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.74 (d, J = 8.0, 1H), 7.68 (d, J = 8.0, 1H), 7.42-7.36 (m, 3H), 7.35-7.26 (m, 3H), 3.57 (s, 2H), 3.26 (br t, J = 4.7, 4H), 2.79 (s, 3H), 2.58 (br t, J = 4.7, 4H).
EXAMPLE 368 1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-2,2,2-trifIuoro-etha!none.
The title compound was prepared according to the procedure for EXAMPLE 257, step A, B and C using trifluoroacetic acid. MS (ESI): mass calculated for 20 C20H18F3N3O2S, 421.44; m/z found, 422.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.0, 1H), 7.68 (d, J = 8.0, 1H), 7.42-7.27 (m, 6H), 3.74-3.70 (m, 2H), 3.65-3.60 (m, 2H), 3.57 (s, 2H), 2.56-2.50 (m, 4H).
EXAMPLE 369 CpX)jO 231 544938 2-(4-Morpholin-4-ylmethyl-phenoxy)~benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 259, step C and D using morpholine. MS (ESi): mass caicuiated for 5 C18Hi8N202S, 326.42; m/z found, 327.4 [M+Hf. 1H NMR (500 MHz, CDCi3): 7.74 (d, J = 7.7, 1H), 7.67 (d, J = 7.7, 1H), 7.42-7.37 (m, 3H), 7.33-7.25 (m, 3H), 3.72 (t, J = 3.7, 4H), 3.52 (s, 2H), 2.46 (br s, 4H).
EXAMPLE 370 {1-[4-(Benzothiazoi~2-yloxy)-benzyl]-piperidin-4-y!}-carbamic acid phenyl ester.
The title compound was prepared according to the procedure for EXAMPLE 253, step A and B followed by EXAMPLE 258 step C using phenyl isocyanate. 15 MS (ESI): mass calculated for C26H25N3O3S, 459.57; m/z found, 460,4 [M+HJ+. 1H NMR (400 MHz, CDC!3): 7.74 (d, J = 8.0, 1H), 7.67 (d, J = 8.0, 1H), 7.42-7.10 (m, 11H), 4.95 (brd, J = 7,8, 1H), 3.67-3.58 (m, 1H), 3.53 (s, 2H), 2.88-2.82 (m, 2H), 2.21-2.06 (m, 2H), 2.03-1.99 (m, 2H), 1.61-1.44 (m, 2H).
N-{1-[4-(Benzothiazol~2-yloxy)-benzyl]-piperidin-4-yl}-benzenesulfonamide.
The title compound was prepared according to the procedure for EXAMPLE 25 253, step A and B followed by EXAMPLE 258, step C using benzenesulfonyl chloride. MS (ESI): mass calculated for C25H25N3O3S2, 479.62; m/z found, 480.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.86-7.84 (m, 2H), 7.75 (d, J = 8.0, H EXAMPLE 371 232 I 544938 1H), 7.67 (d, J= 8.0, 1H), 7.60-7.48 (m, 3H), 7.41-7.24 (m, 6H), 4.56 (br d, J = 7.8, 1H), 3.48 (s, 2H), 3.26-3.16 (m. 1H), 2.76-2.68 (m, 2H), 2.06-1.97 (m, 2H), 1.78-1.70 (m, 1H), 1.52-1.42 (m, 2H).
EXAMPLE 372 ~~ o 3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propionic acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 10 251, step A and B using 3-amino-propionic acid ethyl ester. MS (ESI): mass calculated for C19H2oN203S, 356.45; m/z found, 357.3 [M+Hf. 1H NMR (400 MHz, CDCIs): 7.74 (d, J = 8.0, 1H), 7.67 (d, J = 8.0, 1H), 7.44-7.25 (m, 6H), 4.21 (br s, 1H), 4.15 (q, J = 7.2, 2H), 3.87 (s, 2H), 2.95 (t, J = 6.3, 2H), 2.58 (t, J = 6.3, 2H), 1.26 (t, J = 7.2, 3H).
EXAMPLE 373 O 3-[4-(Benzothiazoi-2-yloxy)-benzylaminoJ-propionic acid.
The title compound was prepared according to the procedure for EXAMPLE 372, and EXAMPLE 250, step D. MS (ESI): mass calculated for Ci/H^C^S, 328.39; m/z found, 329.3 [M+Hf. 1H NMR (400 MHz, DMSO): 7.87 (d, J = 8.0, 1H), 7.62 (d, J= 8.0, 1H), 7.44-7.23 (m, 6H), 3.77 (s, 2H), 2.72 (t, J= 6.6, 2H), 2.29 (t, J = 6.6, 2H). 233 544938 EXAMPLE 374 O [(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy!}-piperidine-4-carbonyl)-methyl-aminoj-acetic acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE > 18, step A and EXAMPLE 20 using 3-methyiamino-propionic acid ethyl ester. MS (ESI): mass calculated for C26H31N3O5S, 497.62; m/z found, 498.4 [M+Hf 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.0, 1H), 7.65 (d, J = 8.0, 1H), 7.41-10 7.35 (m, 1H), 7.28-7.23 (m, 3H), 6.99-6.94 (m, 2H), 4.28-4.08 (m, 5H), 3.12 (s, 3H), 3.10-3.04 (m, 1H), 2.98-2.81 (m, 4H), 2,62-2.53 (m, 1H), 2.24-2.12 (m, 2H), 1.97-1.83 (m, 2H), 1.81-1.64 (m, 2H), 1.32-1.24 (m, 3H).
EXAMPLE 376 142-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethylH1,4']bipiperidinyl-4-carboxylic acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 9 20 and EXAMPLE 24 using [1,4']bipiperidiny!-4-carboxyiic acid ethyl ester. MS (ESI): mass calculated for C28H35N3O4S, 509.67; m/z found, 510.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.0, 1H), 7.65 (d, J = 8.0, 1H), 7.41-7.35 (m, 1H), 7.29-7.23 (m, 3H), 6.99-6.92 (m, 2H), 4.16-4.08 (m, 4H), 3.10-3.04 (m 2H), 2.92-2.86 (m, 2H), 2.80 (t, J= 5.9, 1H), 2.36-2.20 (m, 4H), 2.16-2.07 (m, 25 2H), 1.95-1.87 (m, 2H), 1.82-1.57 (m, 7H), 1.24 (t, J = 7.0, 3H). o 234 544938 EXAMPLE 377 O OH 142-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethylH'M,]bipiperidinyl-4-carboxyiic acid.
The title compound was prepared according to the procedure for EXAMPLE 376 and EXAMPLE 250, step D. MS (ESi): mass calculated for C26H31N3O4S, 481.62; m/z found, 482.3 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.76 (d, J = 8.0, 1H), 7.64 (d, J = 8.0, 1H), 7.44-7.38 (m, 1H), 7.32-7.27 (m, 3H), 7.08-7.03 (m, 10 2H), 4.17 (t, J = 5.4, 2H), 3.44-3.36 (m, 2H), 3.24-3.19 (m, 2H), 3.05-2.84 (m, 5H), 2.40-2.20 (m, 3H), 2.14-2.04 (m, 4H), 1.86-1.72 (m, 4H).
EXAMPLE 378 {2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyi}-cyciopropyl-ethyl-amine. 15 I A. (2-f4-(Benzothiazol-2-vloxvVphenvll-ethvl)-cvclopropvl-amine. A mixture of [4-(benzothiazol-2-yloxy)-phenyl]-acetaldehyde (Example 262 step A, 4.2 g, 15.6 mmol), cyciopropylamine (5.4 mL, 78.0 mmoi) and acetic acid (4.5 mL, 78 mmol) in CH2CI2 (156 mL) was stirred at room temperature for 1 h. To the 20 resulting mixture was added NaBH(OAc)3 (6.61 g, 31.2 mmoi). The mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth, rinsed with CH2CI2 (200 mL), washed with 1N NaOH (3 x 50 mL), and concentrated under reduced pressure to yield the crude product as a yellow oil. The crude product was purified on Si02 (330 g; 0-10% CH3OH/CH2CI2) to give 25 a clear oil which crystallized on standing (3.4 g, 71% yield). MS (ESI): mass calculated for C-^His^OS, 310.11; m/z found, 311.2 [M+Hf. 1H NMR (400 235 544938 MHz, CDCIs): 7.76 (d, J = 8.1, 1 H), 7.62 (d, J = 8.1, 1H), 7.46-7.27 (m, 6H), 3.41 (t, J = 7.6, 2H), 3.08 (t, J = 7.6, 2H), 2.38-2.76 (m, 1H), 0.95-0.89 (m, 4H). B. l2-r4-(Benzothiazol-2-vioxv)-phenvl1-ethvl}-cvclopropvl-ethvl-amine. A mixture of acetaidehyde (180 |iL, 3.2 mmol), {2-[4-(benzothiazol-2-yloxy)-5 phenyl]-ethyl}-cyclopropyl-amine (500 mg, 1.6 mmol) in CH2CI2 (32 mL) was stirred at room temperature for 1 h. To the resulting mixture was added NaBH(OAc)3 (1.02 g, 4.8 mmol). The mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth, rinsed with CH2CI2 (100 mL), and concentrated under reduced pressure to yield the crude product as a yellow oil. 10 The crude product was purified on SiC>2 (40 g; 0-10% CH3OH/CH2Ci2) to give a clear oil (465 mg, 86% yield). MS (ESi): mass calculated for C20H22N2OS, 338.15; m/z found, 339.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.66 (d, J = 8.1, 1H), 7.58 (d, J = 8.1, 1H), 7.31 (t, J = 8.1, 1H), 7.23-7.15 (m, 5H), 2.80 (s, 4H), 2.72 (dd, J = 7.3, 7.1, 2H), 1.78-1.70 (m, 1H), 1.05 (t, J = 7.1, 3H), 0.50-0.36 15 (m, 4H).
EXAMPLE 379 3„({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-met^yl-20 propionic acid trifluoromethansulfonic acid salt.
A. 3-f{2-f4-fBenzothiazol-2-vloxvVphenvll-ethvl)-cvclopropyl-aminoV2-methvi-propionic acid methyl ester. To a solution of {2-[4-(benzothiazol-2-yioxy)-phenyl]-ethyl}-cyclopropyl-amine (500 mg, 1.6 mmol) in CH3CN (10 mL) at 25 room temperature was added A/,A/-diisopropylethylamine (349 jiL, 2 mmol), followed by 3-bromo-2-methyl-propionic acid methyl ester (362 mg, 2 mmol). The resulting mixture was heated at 60 °C overnight. The mixture was cooled and dissolved in CH2CI2 (100 mL), washed with sat. aq. NaHC03 (1 x 25 mL) and H2O (2 x 25 mL), dried (Na2S04) and concentrated under reduced 30 pressure to yield the crude product as a off-white solid. The crude product was 236 544938 purified on Si02 (40 g; 0-10% CH3OH/CH2CI2) to give a pale off-white soiid (158 mg, 39% yield). MS (ESI); mass calculated for C23H26N2C>3S, 410.17; m/z found, 411.3 [M+Hf. 1H NMR (400 MHz, CD3OD); 7.73 (d, J= 8.3, 1H), 7.65 (d, J= 8.3, 1H), 7.38 (t, J = 8.1, 1H), 7.28-7.23 (m, 5H), 3.66 (s, 3H), 3.01 (dd, 5' J = 8.8,3.8, 1H), 2.89-2.76 (m, 5H), 3.60 (dd, J = 6.6, 6.1, 1H), 1.84-1.78 (m, 1H), 1.12 (d, J= 7.1, 3H), 0.51-0.30 (m,4H).
B. 3-(r(2-r4-(,Benzothiazol-2-vloxv)-phenvn-ethvl)-cvclopropvl-amino)-2-methvl-propionic acid trifluoromethansulfonic acid salt. To a solution of 3-({2-[4-(ben?othiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methyl-propionic 10 acid methyl ester (158 mg, 0.38 mmol) in 3:1 ;1 THF/CH3OH (13 mL), was added a solution of lithium hydroxide (37 mg, 1.54 mmol) in H20 (3 mL), The reaction solution was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in CH3OH and purified by reversed-phase HPLC. The desired fractions were collected 15 and concentrated under reduced pressure, giving the the title compound as a clear oil (179 mg, 92% yield). MS (ESI): mass calculated for C22H24N2O3S, 396.15; m/z found, 397.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.78 (d,J = 8.3, 1H), 7.64 (d, J= 8.1, 1H), 7.51-7.27 (m, 6H), 3.83 (t, J= 12.4, 1H), 3.55 (t, J = 8.1, 2H), 3.37 (d, J-13.1, 1H), 3.25 (t, J = 8.8, 2H), 3.21-3.11 (m, 1H), 20 2.99-2.90 (m, 1H), 1.33 (d, J = 7.3, 3H), 1.17-0.97 {m, 4H).
/ EXAMPLE 380 2-({2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-cyclopropylmethyt-amino)-25 ethanol.
The title compound was prepared according to the procedure for EXAMPLE 378, step A using cyclopropyl-methylamine and EXAMPLE 379, step A using 2-bromoethanol. MS (ESI): mass calculated for C21H24N2O2S, 368.16; m/z 30 found, 369.3 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.70 (d, J= 8.1, 1H), 7.62 237 544938 (d, J = 8.1, 1H), 7.34 (t, J = 7.3, 1H), 7.27-7.18 (m, 5H), 3.56 (t, J = 5.3, 2H), 2.92-2.86 (m, 2H), 2.84-2.73 (m, 4H), 2.49 (d, J= 6.6, 2H), 0.92-0.81 (m, 1H), 0.55-0.49 (m, 2H), 0.16-0.09 (m, 2H).
EXAMPLE 381 2-[2-({2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-ethoxy]-ethanol.
The title compound was prepared according to the procedure for EXAMPLE 380. MS (ESI): mass calculated for CgsHasNaOsS, 412.18; m/z found, 413.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.64 (d, J= 8.3, 2H), 7.41 (d, J= 8.3, 2H), 7.31 (t, J= 8.3, 1H), 7.25-7.17 (m, 3H), 4.08 (brs, 1H), 3.84-3.68 (m, 6H), 3.59-3.49 (m, 2H), 3.26-3.16 (m, 2H), 1.11-0.99 (m, 1H), 0.79-0.70 (m, 2H), 15 0.55-0.48 (m, 2H).
EXAMPLE 382 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethy!-amino)-20 propan-1-ol.
The title compound was prepared according to the procedure for EXAMPLE 378, steps A using cyclopropyl-methyiamine and EXAMPLE 379, step A using 3-bromo-propan~1-ol. MS (ESI): mass calculated for C^^eNzOzS, 382.17; 25 m/z found, 383.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.70 (d, J = 8.1, 1H), 7.62 (d, J = 8.1, 1H), 7.34 (t, J = 8.1, 1H), 7.27-7.18 (m, 5H), 3.77 (t, J = 5.3, 238 544938 2H), 2.84-2,76 (m, 6H), 2.43 (d, J = 6.6, 2H), 1,72-1,65 (m, 2H), 0.94-0.83 (m, 1H), 0.57-0.49 (m, 2H); 0.18-0.11 (m, 2H), EXAMPLE 383 {2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-cycIopropylmethyI-(3-tetrazol-2-yl-propyl)-amine trifluoromethansulfonic acid salt.
To a solution of 3-({2-[4-(benzothiazol-2-yIoxy)-phenylj-ethyl}-10 cyclopropylmethyl-amino)-propan-1-ol (Example 382, 220 mg, 0.58 mmol) and 2H-tetrazole (61 mg, 0.87 mmol) in CH2C!2 (12 mL) was added polymer-supported triphenylphosphine (290 mg, 0.87 mmoi) and di-tert-butyi azodicarboxylate (200 mg, 0.87 mmol). The reaction mixture was stirred at room temperature for 1 h, filtered and the collected solids were washed with 15 CH2CI2 (10 mL). The filtrate was concentrated under reduced pressure to yield the crude product as a light yellow oil. The crude product was dissolved in CH3OH and purified by reversed-phase HPLC. The desired fractions were collected and concentrated under reduced pressure, giving the title compound as a clear oil (100 mg, 40% yield). MS (ESI): mass calculated for 20 CasHseNeOS, 434.19; m/z found, 435.3 [M+Hf, 1H NMR (400 MHz, CDCI3): 8.75 (s, 1H), 7.75 (d, J= 8.1, 1H), 7.60 (d, J= 8.1, 1H), 7.45-7.32 (m, 5H), 7,28 (t, J = 8.1, 1H), 3.54-3.40 (m, 4H), 3.29-3.25 (m, 2H), 3,19 (d, J = 7.3, 2H), 3.09 (t, J = 8.6, 2H), 2.56-2.47 (m, 2H), 1.16-1,05 (m, 1H), 0.78-0.71 (m, 2H), 0.46-0.40 (m, 2H).
EXAMPLE 384 239 544938 {2-[4-(Benzothiazol-2-y!oxy)-phenyl]-ethy)}-cyclopropyl-(3-pyrroI-1-yl-propyl)-amine.
The title compound was prepared according to the procedure for EXAMPLE 5 379, step A using 1-(3-bromo-propyl)-1H-pyrroie. MS (ESI): mass calculated for CzsHzzNaOS, 417.19; m/z found, 418.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.65 (d, J= 7.6, 1H), 7.57 (d, J=8.1, 1H), 7.30 (t, J = 8.1, 1H), 7.21-7.13 (m, 5H), 6.57 (t, J = 2.0, 2H), 6.07 (t, J = 2.0, 2H), 3.80 (t, J = 7.1, 2H), 2.80-2.69 (m, 4H), 2.57 (t, J = 7.1, 2H), 1.98-1.88 (m, 2H), 1.74-1.67 (m, 1H), 0.47-0.40 10 (m, 2H), 0.37-0.31 (m, 2H).
EXAMPLE 385 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyimethyl-amino)-15 butyronitrile.
The title compound was prepared according to the procedure for EXAMPLE 378, step A using cyclopropyl-methyiamine and EXAMPLE 319, step A ^jsing 4-bromo-butyronitrile. MS (ESI): mass calculated for C23H25N3OS, 391.17; m/z 20 found, 392.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.70 (d, J = 8.1, 1H), 7.63 (d, J = 8.1,1 H), 7.35 (t, J = 8.1, 1H), 7.27-7.20 (m, 5H), 2.77-2.73 (m, 4H), 2.64 (t, J = 6.6, 2H), 2.39 (d, J = 6.3, 2H), 2.29 (t, J = 6.8, 2H), 1.74-1.66 (m, 2H), 0.89-0.78 (m, 1H), 0.55-0.48 (m, 2H), 0.13-0.08 (m, 2H).
EXAMPLE 386 O 240 544938 1 -{2-[4-(BenzothiazoI-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxyiic acid (2-cyano-ethyl)-amide.
The title compound was prepared according to the procedure for EXAMPLE 5 33, step B, using 3-amino-propionitriie, MS (ESI): mass calculated for C24H26N4O2S, 434.18; m/z found, 435.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.74 (d, J = 8.3, 1H), 7.67 (d, J= 8.1, 1H), 7.40 (t, J= 8.1, 1H), 7.32-7.24 (m, 5H), 6.39 (t, J = 6.6, 1H), 3.51 (dd, J = 6.3, 6.1, 2H), 3.11-3.00 (m, 2H), 2.89-2.82 (m, 2H), 2.69-2.58 (m, 4H), 2.23-2.13 (m, 1H), 2.08 (t, J= 12.1, 2H), 1.94-10 1.76 (m,4H).
EXAMPLE 387 {2-[4-(Benzothiazol-2-yloxy)~phenyl]-ethyl}-cyclopropySmethyl-[3-(2H-tetrazol-5-15 yi)-propyl]-amine.
To a solution of 4-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-butyronitrile (Example 385, 250 mg, 0.6 mmo|) in toluene (32 mL) at room temperature was added trimethylaiuminum (2.0 M 20 solution in toluene, 1.53 mL, 3.08 mmol), followed by azidotrimethylsilane (404 fiL, 3.08 mmol). The resulting mixture was heated at 80 °C for 18 h. The mixture was cooled to room temperature and diluted with CH2CI2 (200 mL), washed with sat. aq. NaHC03 (1 x 25 ml) and H20 (2 x 25 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as an off-25 white solid. The crude product was purified on SiC>2 (40 g; 0-20% CH3OH/CH2CI2) to give an off-white solid (246 mg, 88% yield). MS (ESi): mass calculated for C23H26N6OS, 434.19; m/z found, 435.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 11.25 (br s, 1H), 7.54 (dd, J = 7.8, 5.0, 2H), 7.23 (dd, J = 8.1, 7.3, 1H), 7.19-7.09 (m, 5H), 3.23-3.11 (m, 4H), 3.01-2.90 (m, 4H), 2.83 (d, 241 544938 J= 7.3, 2H), 2.18-2.07 (m, 2H), 1.01-0.91 (m, 1H), 0.57-0.50 (m, 2H)f 0.25-0.18 (m, 2H).
EXAMPLE 388 3-[5-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-piperidin-4-yl)-tetrazol-1-yi]-propionitrile.
To a stirred suspension of 1-{2-[4-(benzothiazol-2-yloxy)-phenyi]-ethyl}-10 piperidine-4-carboxylic acid (2-cyano-ethyI)-amide (Example 386, 500 mg, 1.15 mmol) and triphenylphosphine (755 mg, 2.88 mmol) in anhydrous CH3CN (10 mL) at 0 °C were added diisopropyt azodicarboxyiate (567 jjlL, 2.88 mmol) and 2 min later, azidotrimethylsilane (399 |oJL, 3.04 mmol) over 20 min. The reaction mixture was allowed to warm to room temperature over 30 min then 15 was stirred for an additional 14 h. The reaction mixture was added to ice H20 (20 mL) and extracted with CH2CI2 (2 x 25 mL). The combined organic layers were dried (Na2S04) and concentrated. The residue was purified on Si02 (40 g; 0-15% CH30H/CH2CI2) to give an off-white solid (439 mg, 83% yield)/ MS (ESI): mass calculated for C24H25N70S, 459.18; m/z found, 460.5 [M+H]+. 1H 20 NMR (400 MHz, CDCIg): 7.71 (d, J = 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7.38 (t, J = 7.8, 1H), 7.31-7.23 (m, 5H), 4.62 (t, J = 6.8, 2H), 3.20-3.10 (m, 4H), 3.04-2.94 (m, 1H), 2.91-2.82 (m, 2H), 2.73-2.64 (m, 2H), 2.25 (t, J= 10.9, 2H), 2.18-2.05 (m, 2H), 2.04-1.95 (m,2H).
EXAMPLE 389 242 544938 {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyc!opropyl-[3-(2H-tetrazoI-5-yl)-propylamine.
The title compound was prepared according to the procedure for EXAMPLE 5 387. MS (ESI): mass calculated for C2oH24N6OS, 420.17; m/z found, 421.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 13.02 (brs, 1H), 7.50 (dd, J-8.1, 3.5, 2H), 7.20 (t, J= 8.1, 1H), 7.12-7.04 (m, 5H), 2,95-2.77 (m, 8H), 2.06-1.93 (m, 3H), 0.60-0.48 (m, 4H).
EXAMPLE 390 O 1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxyiic acid (2-hydroxy-1,1 -dimethyi-ethyl)-amide.
The title compound was prepared according to the procedure for EXAMPLE 33, steps B and C using 2-amino-2-methyl-propan-1-ol. MS (ESI): mass calculated for Cas^^C^S, 453.21; m/z found, 454.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.75 (d, J = 8.1, 1H), 7.68 (d, J = 8.1, 1H), 7.40 {t, J= 8.V, 1H), 7.32-7.25 (m, 5H), 5.83 (s, 1H), 5.06 (brs, 1H), 3.59 (s, 2H), 3.14-3.06 (m, 2H), 20 2.91-2.84 (m, 2H), 2.70-2.63 (m, 2H), 2.20-2.10 (m, 3H), 1.95-1.74 (m, 4H), 1.32 (s, 6H).
EXAMPLE 391 {2-[4-(Benzothiazoi-2-yloxy )-phenyl]-ethyl}-cyciopropylmethyl-[3-( 1H-[1,2,4]triazo!-3-yl)-propyl]-amine trifluoromethansulfonic acid salt. 243 544938 A. 4-({2-f4-CBenzothiazol-2-vloxvVphenvn-ethvl)-cvclopropvlmethvl-aminoV butvrimidic acid ethvl ester hydrochloride salt. A solution of 4-({2-[4-(benzothiazol-2-yloxy)~phenyl]-ethyl}-cyclopropylmethyI-amino)-butyronitrile (Example 385, 932 mg, 2.38 mmol) in absolute ethanol (5 mL) and diethyl ether (10 mL) was treated with bubbled hydrogen chloride gas for 1 h. The resulting suspention was filtered and washed with ether to give the title compound (1.12 g, 92% yield). Due to instability, the crude materia! was used immediately without purification.
B. f2-r4-fBenzothiazol-2-vloxvVphenvn-ethvlVcyclopropvimethyl-f3-( 1H-ri.2.41triazol-3-yi)-propyn-amine trifluoromethansulfonic acid salt. To a solution of 4-({2-[4-(benzothiazol-2-y!oxy)-phenyl]-ethyl}-cyciopropylmethyl-amino)-butyrimidic acid ethyl ester hydrochloride salt (511 mg, 1 mmol) in ethanol (4.5 mL) was added triethylamine (375 jxL, 2.7 mmol), followed by a solution of formic hydrazide (60 mg, 1 mmol) in ethanol (4.5 mL). The resulting mixture was stirred at room temperature for 2 h and then at reflux for 1 h. The mixture was cooled and diluted with CH2CI2 (1500 mL), washed with sat. aq. NaHC03 (1 x 25 mL) and H20 (2 x 25 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a off-white solid. The crude product was purified on Si02 (40 g; 0-15% CH3OH/CH2CI2) to give a off-white solid (317 mg, 73% yield). MS (ESI): mass calculated for C24H27N5OSy 433.19; m/z found, 434.4 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.91 (OH), 7.68 (d, J = 7.8, 1H), 7.63 (d, J = 8.1, 1H), 7.34 (t, J = 8.1, 1H), 7.25-7.19 (m, 5H), 2.90-2.76 (m, 6H), 2.72 (t, J = 6.3, 2H), 2.46 (d, J= 6.6, 2H), 2.00-1.90 (m, 2H), 0.93-0.82 (m, 1H), 0.56-0.49 (m, 2H), 0.16-0.10 (m, 2H).
EXAMPLE 392 {2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyclopropylmethyl-[3-(5-methyl-1H-[1 ,2,4]triazol-3-yl)-propyl]-amine. 244 544938 The title compound was prepared according to the procedure for EXAMPLE 391, step B using acetic hydrazide. MS (ESi): mass calculated for C25H29N50S, 447.21; m/z found, 448.4 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.65 (dd, J = 8.1, 8.1, 2H), 7.35 (t, J = 8.1, 1H), 7.27-7.21 (m, 5H), 3.01-2.94 5 (m, 2H), 2.93-2.84 (m, 4H), 2.81 (t, J = 6.6, 2H), 2.61 (ds J = 6.8, 2H), 2.37 (sf 3H), 2.07-1.97 (m, 2H), 1.01-0.89 (m, 1H), 0.62-0.53 (m, 2H), 0.25-0.17 (m, 2H).
EXAMPLE 393 {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}~cyclopropylmethyl-[3-(5-phenyl-1H-[1,2,4]triazoi-3-yl)-propyl]~amine.
The title compound was prepared according to the procedure for EXAMPLE 15 391, step B using benzoic acid hydrazide. MS (ESI): mass calculated for C30H31N5OS, 509.22; m/z found, 510.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 8.06 (dd, J= 16.8, 0.5, 2H), 7.70 (d, J = 8.1, 1H), 7.63 (d, J= 8.1, 1H), i.42-7.30 (m, 4H), 7.28-7.20 (m, 5H), 2.99-2.87 (m, 6H), 2.85 (t, J = 6.6, 2H), 2.58 (d, J- 6.8, 2H), 2.09-2.00 (m, 2H), 1.00-0.89 (mf 1H), 0.61-0.53 (m, 2H), 0.23-20 0.16 (m, 2H).
EXAMPLE 394 245 544938 2-(4-{2-[4-(1-Methyl-1H-tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazole trifluoroacetic acid salt.
To a solution of 2-(4-{2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-ethyI}-phenoxy)-5 benzothiazole (Example 262, 80 mg, 1.97 mmol) in DMF (20 ml) was added K2CO3 (256 mg, 1.85 mmol) and dimethyl carbonate (360 fiL, 4.27 mmol). The reaction mixture was stirred at room temperature for 18 h, filtered and concentrated under reduced pressure. The crude product was dissolved in CH3OH and purified by reversed-phase HPLC. The desired fractions were 10 collected and concentrated under reduced pressure, giving the title compound as a colorless oil (289 mg, 27% yield). MS (ESI): mass calculated for C22H24N6OS, 420.17; m/z found, 421.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.72 (d, J = 7.8, 1H), 7.58 (d, J = 7.8, 1H), 7.44-7.28 (m, 5H), 7.25 (t, J = 8.1, 1H), 4.06 (s, 3H), 3.80 (d, J= 12.1, 1H), 3.66-3.35 (m, 4H), 3.28-3.17 (m, 2H), 15 3.16-3.08 (m, 2H), 2.33-2.23 (m, 2H), 2.22-2.07 (m, 2H).
EXAMPLE 395 2-(4-{2-[4-(2-Methyl-2H-tetrazol-5~yl)-piperidin-1-yi]-ethyl}-phenoxy)-20 benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 394. MS (ESI): mass calculated for C22H24N6OS, 420.17; m/z found, 421.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.75 (d, J = 7.8, 1H), 7.60 (d, J = 7.8, 25 1H), 7.46-7.33 (m, 5H), 7.28 (t, J= 7.8, 1H), 4.31 (s, 3H), 3.79 (d, J= 13.4, 1H), 3.62-3.06 (m, 8H), 2.48-2.30 (m, 2H), 2.15-2.02 (m, 2H). 246 544938 EXAMPLE 396 1-{2-[4-(Benzothiazof-2-yloxy)-phenyi]-ethyl}-piperidine-4-carboniiriIe.
The title compound was prepared according to the procedure for EXAMPLE 262, using piperidine-4-carbonitrile. MS (ESi): mass calculated for C2iH2iN3OS, 363.14; m/z found, 364.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.63 (d, J = 7.6, 1H), 7.55 (d, J = 7.6, 1H), 7.28 (t, J = 8.1,1 H), 7.20-7.12 (m, 5H), 2.71 (dd, J = 7.1, 3.3, 2H), 2.68-2.55 (m, 3H), 2.52 (dd, J = 7.1, 3.3, 2H), 10 2.37-2.25 (m, 2H), 1.91-1.73 (m, 2H).
EXAMPLE 397 2-(4-{2-[4-(1H-[1,2,3]Triazol-4-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazole. 15 I To a solution of trimethylsilyidiazomethane (1.8 mL, 3.6 mmol) in diethyl ether (30 mL) at 0 °C under nitrogen was added dropwise n-butyllithium (2.5 M in hexane, 1.44 mL, 3.6 mmol) and the mixture was stirred at 0 °C for 20 min. To the resulting solution was added dropwise a solution of 1-{2-[4-(benzothiazol-2-20 yloxy)-phenyl]-ethyl}-piperidine-4-carbonitrile (Example 396, 1.09 g, 3.0 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. The mixture was treated with sat. aq. NH4CI and extracted with CH2CI2 (2 x 100 mL). The extracts were washed with H20 (2 x 25 mL), dried (NazSC^) and concentrated under reduced pressure to yield the crude product as an off-white 25 solid. The crude product was purified on Si02 (40 g; 0-10% CH3OH/CH2CI2) to give an off-white solid (768 mg, 54% yield). MS (ESI): mass calculated for C22H23N5OS, 405.16; m/z found, 406.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 247 544938 7.63 (d, J = 8.1, 1H), 7.56 (d, J = 8.1, 1H), 7.42 (s, 1H), 7.29 (t, J = 7.8, 1H), 7.23-7.14 (m, 5H), 4.67 (brs, 1H), 3.04 (d, J= 11.9, 2H), 2.84-2.70 (m, 3H), 2.63-2.56 (m, 2H), 2.16 (t, J= 11.1, 2H), 1.97 (d, J= 12.6, 2H), 1.82-1.70 (m, 2H). 4-{2-[4-(Benzothiazol-2-yloxy)-phenylfethyIamino}-butyric acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 378, step A using 4-a mi no-butyric acid ethyl ester. MS (ESI): mass calculated for C21H24N2O3S, 384.15; m/z found, 385,3 [M+Hf, 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.66 (d, J= 8.1, 1H), 7.38 (t, J= 8.1, 1H), 7.31-7.22 (m, 5H), 6.67 (br s, 1H), 4,12 (dd, J = 7.3, 7.1, 2H), 2,95-2.80 (m, 2H), 15 2.69 (t, J = 6.8, 2H), 2.35 (t, J = 7.3, 2H), 2,29 (t, J = 7.3, 2H), 1.86-1.77 (m, 2H), 1.25 (t, J = 7.1, 3H).
EXAMPLE 399 4-({2-[4-(B.enzothiazol-2-yloxy)-phenyl]-ethy!}-cyclopropyimethyl-amino)-butyric acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 378, step A using cyclopropyl-methyiamine and EXAMPLE 379, step A using 25 4-bromo-butyric acid ethyl ester. MS (ESI): mass calculated for C25H30N2O3S, 438.20; m/z found, 439.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.35 (t, J = 8.1, 1H), 7,27-7.20 (m, 5H), 6,67 (br s, EXAMPLE 398 o 248 544938 1H), 4.10 (dd, J = 7.1, 7.1, 2H), 2.83-2.71 (m, 4H), 2.60 (t, 7.1, 2H), 2.40 (t, J = 6.6, 2H), 2.31 (t, J = 7.3, 2H), 1.81-1.72 (m, 2H), 1.23 (t, J = 7.1, 3H), 0.88-0.79 (m, 1H), 0.52-0.45 (m, 2H), 0.13-0.07 (m, 2H).
EXAMPLE 400 2-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyI-amino)-propyl]-isoiridole-1,3-dione.
The title compound was prepared according to the procedure for EXAMPLE 378, steps A using cyclopropyl-methyiamine and EXAMPLE 379, step A using 2-(3-bromo-propyl)-isoindole-1,3-dione. MS (ESi): mass calculated for C30H29N3O3S, 511.19; m/z found, 512.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.84-7.77 (m, 2H), 7.72-7.63 (m, 3H), 7.60 (d, J = 7.8, 1H), 7.34 (t, J = 8.1, 1H), 7.27-7.18 (m, 5H), 3.71 (t, J = 7.1, 2H), 2.82-2.70 (m, 4H), 2.65 (t, J = 7.6, 2H), 2.39 (d, J = 6.6, 2H), 1.88-1.79 (m, 2H), 0.87-0.76 (m, 1H), 0.50-0.42 (m, 2H), 0.12-0.06 (m, 2H). 4-({2~[4-(Benzothiazol-2-yloxy)-phenyl]-ethy!}-cyciopropylmethyI-amino)-butyric acid.
The title compound was prepared from EXAMPLE 399 followed by the 25 procedure for EXAMPLE 379, step B. MS (ESI): mass calculated for C23H26N2O3S, 410.17; m/z found, 411.4 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.42 (d, J = 7.8, 1H), 7.31 (d, J = 7.8, 1H), 7.16-7.10 (m, 2H), 7.07 (t, J = 7.8, / EXAMPLE 401 249 544938 1H), 7.04-7.00 (m, 2H), 6.96 EXAMPLE 402 1-(3-{2-[4-(Benzothiazol-2-ySoxy)-phenyi]-ethylamino}-propyl)-pyrrolidin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 10 378, step A using 1-(3-aminio-propyl)-pyrrolidin-2-one. MS (ESi): mass calculated for C22H25N3O2S, 395.17; m/z found, 396.4 [M+H]\ 1H NMR (400 MHz, CDCI3): 7.67 (d, J = 8.1, 1H), 7.60 (d, J = 8.1, 1H), 7,32 (t, J = 7.8, 1H), 7.28-7.15 (m, 5H), 5.61 (brs, 1H), 3.34-3.25 (m, 4H), 2.94-2,81 (m, 4H), 2.65 (t, J = 7.3, 2H), 2.32 (t, J = 7.8, 2H), 1.94 (t, J - 7.3, 2H), 1.79-1.69 (m, 2H).
N-1 ~{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N 1 -cyciopropylmethyl-propane-1,3-diamine.
To a solution of 2-[3-({2-[4-(benzothiazol-2-yloxy)-pheny!J-ethyl}-cyciopropy!methyl-amino)-propyl]-isoindole-1,3-dione (Example 400, 3.0 g, 5.86 mmol) in EtOH (12 mL) was added hydrazine (220 jiL, 7.03 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was 25 dissolved in CH2CI2 (200 mL), washed with saturated NaHCC>3 (2 x 20 ml), H2O (1 x 20 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a off-white solid. The crude product was purified on Si02 EXAMPLE 403 250 544938 {330 g; 0-10% 2 M NH3 in CH3OH/CH2CI2) to give a clear oil (2.13 g, 96% yield). MS (ESI): mass calculated for C22H27N3OS, 381.2; m/z found, 382.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.68 (d, J = 8.1, 1H), 7.58 (d, J = 8.1, 1H), 7.31 (t, J = 8.1, 1H), 7.24-7.16 (m, 5H), 2.79-2.71 (m, 4H), 2.67 (t, J = 6.8, 5 2H), 2.59 (t, J = 6.8, 2H), 2.37 (d, J = 6.6, 2H), 2.07 (s, 2H), 1.62-1.52 (m, 2H), 0.87-0.77 (m, 1H), 0.50-0.44 (m, 2H), 0.12-0.06 (m, 2H).
EXAMPLE 404 5-({2-[4-(Benzothiazol~2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-pentanoic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 379, step A using 5-bromo-pentanoic acid methyl ester. MS (ESI): mass 15 calculated for C24H28N2O3S, 424.18; m/z found, 425.3 [M+Hf, 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.36 (t, J = 8.1, 1H), 7.27-7.20 (m, 5H)f 3.65 (s, 3H), 2.85-2.80 (m, 4H), 2.66 (t, J = 7.6, 2H), 2.33 (t, J = 7.6, 2H), 1.81-1.75 (m, 1H), 1.67-1.50 (m, 4H), 0.52-0.40 (m, 2H), 0^43-0.37 (m, 2H).
EXAMPLE 405 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyt}-cyclopropylmethyl-amino)-propylj-acetamide.
To a solution of N-1-{2-[4-(Benzothiazol-2-yioxy)-pheny!]-ethyi}-N1-cycIopropylmethyl-propane-1,3-diamine (Example 403, 180 mg, 0.47 mmol) in A 251 544938 CH2CI2 (10 mL) was added triethylamine (131 jliL, 0,94 mmol), followed by acetic anhydride (76 |nL, 0.71 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was dissolved in CH2CI2 (100 mL), washed with sat. NaHC03 (2x15 ml), H20 (1x15 mL), dried (Na2S04) and concentrated under reduced pressure to yield the crude product as a off-white solid. The crude product was purified on Si02 (12 g; 0-10% CH3OH/CH2CI2) to give a white solid (154 mg, 77% yield). MS (ESI): mass calculated for C24H29N3OS, 423.2; m/z found, 424.4 [M+H]\ 1H NMR (400 MHz, CDCI3): 9.69 (brs, 1H), 7.67 (d, J = 8.1, 1H), 7.62 (d, J = 8,1, 1H), 7.33 (t, J = 8,1, 1H), 7.27-7.17 (m, 5H), 3.27 (dd, J = 6.6, 5.6, 2H), 2.96-2,89 (m, 2H), 2.87-2.81 (m, 2H), 2.78 (t, J= 6.8, 2H), 2.53 (d, J= 6.8, 2H), 1.88 (s, 3H), 1.76-1.67 (m, 2H), 0.94-0.83 (m, 1H), 0.60-0.53 (m, 2H), 0.21-0.15 (m, 2H).
EXAMPLE 406 Morpholine-4-carboxylic acid [3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethy!}-cyclopropylmethyl-amino)-propyl]-amide.
The title compound was prepared according to the procedure for EXAMPLE 405, using morpholine-4-carbonyl chloride. MS (ESi): mass calculated for C28H34N4O3S, 494.24; m/z found, 495.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.69 (t, J - 8.5, 2H), 7,41-7.23 (m, 6H), 6.85 (br s, 1H), 3.68-3.60 (m, 4H), 3.51-3.40 (m, 6H), 3.39-3.27 (m, 4H), 3.26-3.17 (m, 2H), 3.09-3.01 (m, 2H), 2.19-2.06 (m, 2H), 1.25-1.14 (m, 1H), 0.85-0.76 (m, 2H), 0.53-0.45 (m, 2H).
EXAMPLE 407 252 544938 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyI-amino)-propyl]-methanesulfonamide, The title compound was prepared according to the procedure for EXAMPLE 5 405, using methanesulfonyt chloride. MS (ESI): mass calculated for C23H29N3O3S2! 459.17; m/z found, 460.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.67 (t, J = 8.6, 2H), 7.39-7.17 (m, 6H), 7.06 (brs, 1H), 3.43-3.09 (m, 8H), 3.07-2.98 (m, 2H), 2.96 (s, 3H), 2.20-2.07 (m, 2H), 1.23-1.11(m, 1H), 0.79-0.67 (m, 2H), 0.49-0.41 (m, 2H).
EXAMPLE 408 -({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cycfopropyl-amino)~pentanoic acid.
The title compound was prepared from EXAMPLE 379 and the procedure for EXAMPLE 404, step B. MS (ESI): mass calculated for C23H26N2O3S, 410.17; m/z found, 411.3 [M+Hf. 1H NMR (400 MHz, CDCi3): 12.39 (brs, 1H),^.71 (d, J = 7.8, 1H), 7.62 (d, J = 7.8, 1H), 7.35 (t, J = 7.8, 1H), 7.31-7.20 (m, 5H), 20 3.04-2.90 (m, 4H), 2.82 (t, J = 7.8, 2H), 2.30 (t, J = 6.8, 2H), 1.98-1.91 (m, 1H), 1.72-1.54 (m, 4H), 0.83-0.76 (m, 2H), 0.63-0.55 (m, 2H).
EXAMPLE 409 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropyl-amino)-propyl]-pyrroIidin-2-one. 253 544938 A mixture of 1-(3-{2-[4-(benzothiazoi-2-yloxy)-phenyl]-ethylamino}-propyl)-pyrrolidin-2-one (Example 402, 500 mg, 1.26 mmol), acetone (185 ]j.L, 2.52 mmol) in CH2CI2 (25 mL) was stirred at room temperature for 1 h. To the resulting mixture was added NaBH(OAc)3 (536 mg, 2.52 mmol). The mixture 5 was stirred at room temperature for 16 h, filtered through diatomaceous earth, washed with CH2CI2 (100 mL) and concentrated under reduced pressure to yield the crude product as a yellow oil. The crude product was purified on Si02 (40 g; 0-10% CH3OH/CH2CI2). The desired fractions were combined and concentrated under reduced pressure to give a clear oil which crystallized on 10 standing (290 mg, 53% yield). MS (ESI): mass calculated for C25H31N302S, 437.21; m/z found, 438.4 [M+Hf. 1H NMR (400 MHz, CDCI3); 7.73 (d, J= 8.3, 1H), 7.66 (d, J = 8.3, 1H), 7.38 (t, J = 8.3, 1H), 7.28-7.23 (m, 5H), 3.35 (t, J = 6.8, 2H), 3.27 (t, J = 7.3, 2H), 3.05-2.95 (m, 1H), 2.78-2.70 (m, 2H), 2.69-2.61 (m, 2H), 2.47 (t, J= 7.3, 2H), 2.37 (t, J= 8.1, 2H), 2.04-1.94 (m, 2H), 1.69-1.58 15 (m, 2H), 0.99 (d, J = 6.8, 6H).
EXAMPLE 410 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-cyclopropylmethyl-amino)-20 propyl]-pyrrolidin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 409, using cyclopropanecarbaldehyde. MS (ESI): mass calculated for C26H3iN302S, 449.21; m/z found, 450.4 [M+Hf. 1H NMR (400 MHz, CDCIS): 7.70 (d, J= 7.8, 1H), 7.64 (d, J= 8.1, 1H), 7.36 (t, J= 7.8, 1H), 7.32-7.21 (m, 5H), 3.38 (t,J = 7.1, 2H), 3.31 (t, J= 7.1, 2H), 3.09-3.02 (m, 2H), 2.95-2.83 (m, 4H), 2.72 (d, J = 7.1, 2H), 2.37 (t, J = 7.8, 2H), 2.05-1.95 (m, 2H), 1.92-1.82 (m, 2H), 1.02-0.91 (m, 1H), 0,66-0.59 (m, 2H), 0.29-0.23 (m, 2H). / 254 544938 EXAMPLE 411 A 1-[3-({2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyi}-cyclopropyl-amino)-propyl]-pyrrolidin-2-one.
To a solution of 1-(3-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyiamino}-propyi)-pyrroIidin-2-one (Example 402, 500 mg, 1.26 mmol) in EtOH (20 mL) was added acetic acid (716 p.L, 1.26 mmo!), molecular sieves (500 mg, 3A), (1-ethoxy-cyclopropoxy)-trimethyl-silane (1.51 mL, 7.58 mmol) and sodium 10 cyanoboronhydride (357 mg, 5.69 mmol). The reaction mixture was heated at reflux for 16 h, cooled and filtered through diatomaceous earth, washed with CH2Ci2 (100 mL) and concentrated under reduced pressure to yield the crude product as a clear oil. The crude product was purified on SiC>2 (40 g; 0-10% CH3OH/CH2CI2). The desired fractions were combined and concentrated 15 under reduced pressure to give a white solid (434 mg, 66% yield).
MS (ESI): mass calculated for C25H29N3O2S, 435.2; m/z found, 436.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 7,8, 1H), 7.64 (d, J = 7.8, 1H), 7.36 (t, J = 7.8, 1H), 7.28-7.19 (m, 5H), 3.36 (t, J = 7.1, 2H), 3.28 (t, J = 7.1, 2H), 2.87-2.80 (m, 4H), 2.67 (t, J = 7.3, 2H), 2.37 (t, J = 7.8, 2H), 2.03-1.94 (m, 2H), 1.82-20 1.70 (m, 3H), 0.53-0.47 (m, 2H), 0.43-0.38 (m, 2H).
EXAMPLE 412 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-propyi-amino)-propy!]-25 pyrrolidin-2-one. 255 544938 The title compound was prepared according to the procedure for EXAMPLE 409, using propionaldehyde. MS (ESI): mass calculated for CasHsiNsC^S, 437.21; m/z found, 438.4 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.72 (d, J= 8.1, 1H), 7.66 (d, J= 8.1, 1H), 7.38 (t, J = 8.1, 1H), 7.29-7.24 (m, 5H), 3.39 (t, J = 5 7.1, 2H), 3.30 (t, J = 7.1, 2H), 2.86-2.80 (m, 4H), 2.64 (t, J = 7.6, 2H), 2.58 (t, J = 7.6, 2H), 2.42-2.35 (m, 2H), 2.07-1.97 (m, 2H), 1.80-1.71 (m, 2H), 1.59-1.47 (m, 2H), 0.92 (d, J= 7.3, 3H).
EXAMPLE 413 4-((1-Acetyf-piperidin-4-y!)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyi}-amino)-butyric acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 15 409, using 1-acetyl-piperidin-4-one. MS (ESI): mass calculated for C28H35N304S, 509.23; m/z found, 510.4 [M+Hf. 1H NMR (400 MHz, CD^Ch): 7.72 (d, J = 8.1, 1H), 7.65 (d, J=8.1, 1H), 7.38 (t, J= 8.1, 1H), 7.29-7.23 (m, 5H), 4.69 (d, J= 13.1, 1H), 4.13 (dd, J- 7.8, 6.8, 2H), 3.85 (d, J=13.4, 1H), 3.09-2.98 (m, 2H), 2.79-2.74 (m, 4H), 2.60 (t, J = 6.8, 2H), 2.52-2.44 (m, 3H), 20 2.04 (s, 3H), 1.85-1.73 (m, 4H), 1.48-1.35 (m, 2H), 1.26 (t, J = 7.1, 3H).
EXAMPLE 414 256 544938 4-((1-Acetyi-piperidin-4-yl)-{2-[4-(benzothiazol-2-yIoxy)-phenyi]~ethyl}-amino)-butyric acid ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 5 409, using 1-methyl-piperidin-4-one. MS (ESI): mass calculated for C27H35N3O3S, 481.2; m/z found, 482.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J= 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.37 (t, J = 8.1, 1H), 7.28-7.19 (m, 5H), 4.12 (dd, J= 7.3, 7.1, 2H), 3.11 (d, J = 12.1, 2H), 2,75-2.69 (m, 4H), 2.58-2.50 (m, 3H), 2.38 (s, 3H), 2.29 (t, J = 7.1, 2H), 2.24-2.15 (m, 2H), 2.03-1.97 10 (m, 2H), 1.73 (t, J = 6.3, 4H), 1.25 (t, J= 7.1, 3H).
EXAMPLE 415 4_({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-methanesuifonyl-amino)-butyric 15 acid.
The title compound was prepared from EXAMPLE 398 following the procedure for EXAMPLE 407 and EXAMPLE 379, step B. MS (ESI): mass calculated for C20H22N2O5S2, 434.1; m/z found, 435.3 [M+Hf. 1H NMR (400 MHz, CDCI3); 20 7.72 (d, J = 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7.38 (t, J = 8.1, 1H), 7.33-7.24 (m, 5H), 3.48 (t, J = 7.6, 2H), 3.20 (t, J = 7.6, 2H), 2.96 (t, J = 7.3, 2H), 2.77 (s, 3H), 2.37 (t, J = 6.6, 2H), 1,91 -1.81 (m, 2H).
EXAMPLE 416 ({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-am!no)-acetic acid. o 257 544938 The title compound was prepared according to the procedure for EXAMPLE 379, step A and B using bromo-acetic acid methyl ester. MS (ESI): mass calculated for C20H20N2O3S, 368.12; m/z found, 369.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.70 (d, J = 8.1, 1H), 7.64 (d, J = 8.1, 1H), 7.37 (t, J= 8.1, 1H), 5 7.31-7.22 (m, 5H), 3.64 (s, 2H), 3.26 (dd, J = 7.6, 3.3, 2H), 2.98 (dd, J = 7.6, 3.3, 2H), 2.50-2.43 (m, 1H), 0.84-0.79 (m, 2H), 0.71-0.65 (m, 2H).
EXAMPLE 417 6-({2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyi}-cyclopropyi-amino)-hexanoic acid ethyl ester.
The titie compound was prepared according to the procedure for EXAMPLE 379, step A using 6-bromo-hexanoic acid ethyl ester. MS (ESI): mass 15 calculated for C26H32N2O3S, 452.21; m/z found, 453.4 [M+H]+. 1H NMR (400 MHz, CDCb): 7.72 (d, J = 8.1, 1H), 7.64 (d, J = 8.1, 1H), 7.36 (t, J = 8.1, 1H), 7.28-7.20 (m, 5H), 4.12 (dd, J= 7.3, 7.1, 2H), 2.87-2.81 (m, 4H), 2.65 (t, J = 7.8, 2H), 2.30 (t, J ~ 7.6, 2H), 1.81-1.74 (m, 1H), 1.69-1.60 (m, 2H), 1.5^-1.50 (m, 2H), 1.37-1.27 (m, 2H), 1.24 (t, J = 7.1, 3H), 0.52-0.46 (m, 2H), 0.43-0.37 20 (m, 2H).
EXAMPLE 418 7_({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-heptanoic 25 acid ethyl ester. 258 544938 The title compound was prepared according to the procedure for EXAMPLE 379, step A using 7-bromo-heptanoic acid ethyl ester. MS (ESI): mass calculated for C27H34N2O3S, 466.23; m/z found, 467.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.71 (d, J= 8.1, 1H), 7.60 EXAMPLE 419 6-({2~[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-cyciopropyl-arnino)-hexanoic The title compound was prepared from EXAMPLE 417 following the procedure for EXAMPLE 379, step B. MS (ESI): mass calculated for C24H28N2O3S, 424.18; m/z found, 425.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 11.17 (brs, 1H), 7.69 (d, J= 8.1, 1H), 7.65 (d, J- 8.1, 1H), 7.39-7.21 (m, 6H), 3.35-^.28 (m, 2H), 3.24-3.10 (m, 4H), 2.53-2.45 (m, 1H), 2.31 (t, J = 7.1, 2H), 1.92-1.81 20 (m, 2H), 1.70-1.61 (m, 2H), 1.44-1.34 (m, 4H), 0.91-0.83 (m, 2H).
EXAMPLE 420 7-({2~[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyclopropyI-amino)-heptanoic 25 acid. acid. 259 544938 The title compound was prepared from EXAMPLE 418 following the procedure for EXAMPLE 379, step B. MS (ESI): mass calculated for C25H30N2O3S, 438.2; m/z found, 439,4 [M+Hf. 1H NMR (400 MHz, CDCI3): 12.57 (brs, 1H), 7.72 (d, J = 8.1, 1H), 7.64 (d, J = 8.1, 1H), 7.36 (t, J = 8.1, 1H), 7.31-7.20 (tn, 5 5H), 3.02-2.90 (m, 4H), 2.78 (t, J = 7.8, 2H), 2,26 (t, J= 7.6, 2H), 1.97-1.90 (m, 1H), 1.67-1.56 (m, 4H), 1.41-1.26 (m, 4H), 0.80-0.73 (m, 2H), 0.62-0.55 (m, 2H).
EXAMPLE 421 N-1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-N1-cyclopropyi-propane-1,3- diamine.
The title compound was prepared according to the procedures for EXAMPLE 15 378, step A using cyclopropylannine, EXAMPLE 379, step A using 2-(3-bromo-propyl)isoindole-1,3-dione and EXAMPLE 403. MS (ESi): mass calculated for C2iH25N30S, 367.17; m/z found, 468.4 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.73 (d, J = 7.6, 1H), 7.65 (d, J = 7.8, 1H), 7.38 (t, J = 7.6, 1H), 7.29-7.2^3 (m, 5H), 2.89-2.82 (m, 4H), 2.71 (t, J = 7.1, 4H), 1.83-1.77 (m, 1H), 1.72-1.64 (m, 20 2H), 1.55 (br s, 2H), 0.54-0.48 (m, 2H), 0.44-0.39 (m, 2H).
EXAMPLE 422 A " N-[3-({2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-cyclopropyl-amino)-propyl]-25 acetamide. 260 544938 The title compound was prepared from EXAMPLE 421 following the procedure for EXAMPLE 405. MS (ESI): mass calculated for C23H27N3O2S, 409.18; m/z found, 410.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.71 (d, J = 8.1, 1H), 7.64 (d, J= 8.1, 1H), 7.36 (t, J = 8.0118, 1H), 7.28-7.21 (m, 5H), 6.77 (brs, 1H), 5 3.26 (dd, J = 6.1, 5.8, 2H), 2.89-2.83 (m, 4H), 2.75 (t, J = 6.8, 2H), 1.89 (s, 3H), 1.84-1.78 (m, 1H), 1.75-1.67 (m, 2H), 0.57-0.51 (m, 2H), 0.47-0.42 (m, 2H).
EXAMPLE 423 N-[3-({2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-cyciopropyl-amino)-propyi]-isobutyramide.
The title compound was prepared according to the procedure for EXAMPLE 421, using isobutyryl chloride. MS (ESI): mass calculated for C25H31N3O2S, 15 437.21; m/z found, 438.4 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.72 (d, J = 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7.37 (t, J = 8.1, 1H), 7.30-7.23 (m, 5H), 6.54 (br s, 1H), 3.30 (dd, J = 6.1, 5.8, 2H), 2.90-2.83 (m, 4H), 2.77 (t, J = 6.3, 2H), 2.31-2.19 (m, 1H), 1.85-1.78 (m, 1H), 1.75-1.67 (m, 2H), 1.12 (d, J = 6.8, 6H)^ 0.58-0.52 (m, 2H), 0.45-0.40 (m, 2H).
EXAMPLE 424 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-benzamide.
The title compound was prepared according to the procedure for EXAMPLE 422, using benzoyl chloride. MS (ESI): mass calculated for C28H29N302S, 261 544938 PCT/US2O04/0243O9 471.20; m/z found, 472.4 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.78-7.67 (m, 4H), 7.61 (d, J = 7.8, 1H), 7.44-7.39 (m, 1H), 7.38-7.31 (m, 3H), 7.25-7.13 (m, 5H), 3.50 (dd, J = 6.1, 5.6, 2H), 2.89-2.77 (m, 6H), 1.85-1.75 (m, 3H), 0.56-0.49 (m, 2H), 0.45-0.38 (m, 2H).
EXAMPLE 425 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyI}-cyciopropyl-amino)-propyl]-4-chloro-benzamide.
The title compound was prepared according to the procedure for EXAMPLE 422, using 4-chloro-benzoyl chloride. MS (ESI): mass calculated for C28H28CIN3O2S, 505.16; m/z found, 506.3 [M+Hf. 1H NMR (400 MHz, CDCi3): 7.80(t, J= 5.0, 1H), 7.68 (d, J= 7.6, 1H), 7.65-7.59 (m, 3H), 7.37-7.29 (m, 3H), 15 7.25-7.15 (m, 5H), 3.47 (dd, J = 6.1, 5.31, 2H), 2.89-2.77 (m, 6H)f 1.84-1.75 (m, 3H), 0.57-0.51 (m, 2H), 0.42-0.36 (m, 2H).
EXAMPLE 426 / N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-methanesulfonamide.
The title compound was prepared according to the procedure for EXAMPLE 422, using methanesulfony! chloride. MS (ESI): mass calculated for 25 C22H27N303S2, 445.15; m/z found, 446.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J= 7.8, 1H), 7.64 (d,J = 7.8, 1H), 7.36 (t, J = 7.8, 1H), 7.28-7.21 (m, 262 544938 5H), 6.03 (br s, 1H), 3.15 (t, J = 6.1, 2H)t 2.88 (s, 3H), 2.87-2.82 (m, 4H), 2.78 (t, J = 6.1, 2H), 1.82-1.71 (m, 3H), 0,58-0.52 (m, 2H), 0.49-0.43 (m, 2H).
EXAMPLE 427 Propane-2-suifonic acid [3-{{2-[4-{benzothiazol-2-yioxy)-pheny!J-etbyl}-cyclopropyi-amino)-propyl]-amide trifluoromethansulfonic acid salt.
The title compound was prepared according to the procedure for EXAMPLE 10 422, using propane-2-sulfonyl chloride. MS (ESI): mass calculated for C24H3-iN303S2i 473.18; m/z found, 474.4 [M+Hf. 1H NMR (400 MHz, CDsOD): 7.65 (d, J= 7.8, 1H), 7.53 (d, J = 8.1, 1H), 7.39-7.16 (m, 6H), 3.44 (t, J= 8.3, 2H), 3.37 (t, J = 8.3, 2H), 3.24-3.19 (m, 2H), 3.16-3.06 (m, 4H), 2.87-2.78 (m, 1H), 2.07-1.94 (m, 2H), 1.67 (d, J = 4.04, 3H), 1.23 (d, J = 6.1, 3H), 1.07-1.00 15 (m, 2H), 0.98-0.91 (m, 2H).
EXAMPLE 428 8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-octanoic acid 20 ethyl ester.
The title compound was prepared according to the procedure for EXAMPLE 379, step A, using 8-bromo-octanoic acid ethyl ester. MS (ESI): mass calculated for CzsHseNaOaS, 480.24; m/z found, 481.4 [M+Hf. 1H NMR (400 25 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.36 (t, J = 8.1, 1H), 7.27-7.20 (m, 5H), 4.11 (dd, J = 7.3, 7.1, 2H), 2.87-2.81 (m, 4H), 2.64 (t, J = 7.3, 2H), 2.28 (t, J = 7.1, 2H), 1.82-1.75 (m, 1H), 1.66-1.58 (m, 2H), 1.56-1.47 263 544938 (m, 2H), 1.36-1.27 (m, 6H), 1.24 EXAMPLE 429 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyt-amino)-propyI]-3-phenyl-urea.
The title compound was prepared according to the procedure for EXAMPLE 10 422, using phenyl isocyanate. MS (ESI): mass calculated for C28H3oN402S, 486.21; m/z found, 487,4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.61 (d, J= 8,1, 1H), 7.57 (d, J = 8.1, 1H), 7.28 (t, J = 8.1, 1H), 7.20-7.09 (m, 10H), 6.89 (t, J = 7.3, 1H), 5.64 (brs, 1H), 3.16-3.09 (m, 2H), 2.70-2.64 (m, 4H), 2.57 (t, J = 7.1, 2H), 1.67-1.60 (m, 1H), 1.60-1.52 (m, 2H), 0.39-0.33 (m, 2H), 0.25-0.20 (m, 8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyl-amino)-octanoic acid.
The title compound was prepared from EXAMPLE 428 following the procedure for EXAMPLE 379, step B. MS (ESI): mass calculated for C26H32N2O3S, 452.21; m/z found, 453.4 [M+Hf. 1H NMR (400 MHz, CDCig): 12.76 (brs, 1H), 7.72 (d, J = 7.6, 1H), 7.63 (d, J = 7.8, 1H), 7.36 (t, J = 7.6, 1H), 7.30-7.21 25 (m, 5H), 3.01-2.88 (m, 4H), 2.77 (t, J = 8.1, 2H), 2.27 (t, J= 7.8, 2H), 1.96-1.88 (m, 1H), 1.66-1.54 (m, 4H), 1.38-1.23 (m, 6H), 0.77-0.70 (m, 2H), 0.61-0.54 (m, 2H). 2H).
EXAMPLE 430 264 51- 'I""" » '•••« 544938 EXAMPLE 431 A Tetrahydro-furan-2-carboxyiic acid [3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-5 ethy!}-cyclopropyl-amino)-propyl]-amide.
To a solution of N-1-{2-[4-(Benzothiazoi-2-yloxy)-phenyi]-ethyl}-N1-cyclopropyl-propane-1,3-diamine (Example 421, 330 mg, 0.9 mmol) in CH2CI2 (18 mL) was added 2-tetrahydrofuroic acid (129 jiL, 1.35 mmol) and Si-carbodiimide (1.05 10 mmol/g, 1.71 g, 1.8 mmol). The reaction mixture was stirred at room temperature overnight, filtered and concentrated. The crude product was purified on Si02 (40 g; 0-10% CH3OH/CH2CI2) to give a white solid (267 mg, 64% yield). MS (ESI): mass calculated for C26H31N3O3S, 465.21; m/z found, 466.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.72 (d, J= 8.1, 1H), 7.64 (d, J = 15 8.1, 1H), 7.36 (t, J = 8.1, 1H), 7.32 (br s, 1H), 7.29-7.21 (m, 5H), 4.32 (dd, J = 6.1, 2.3, 1H), 3.93-3.81 (m, 2H), 3.41-3.31 (m, 1H), 3.30-3,21 (m, 1H), 2.90-2.80 (m, 4H), 2.75 (t, J= 6.8, 2H), 2.32-2.21 (m, 1H), 2.08-1.97 (mt 1H), 1.92-1.77 (m, 3H), 1.76-1.67 (m, 2H), 0.56-0.49 (m, 2H), 0.48-0.41 (m, 2H). y EXAMPLE 432 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-2-hydroxy-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 431 using gycolic acid. MS (ESI): mass calculated for C23H27N3O3S, 425.18; m/z found, 426.3 [M+H]+. 1H NMR (400 MHzs CDCI3): 7.73-7.63 (m, 2H), 7.44 265 544938 (brs, 1H), 7.40-7.33 (m, 1H), 7,29-7.18 (m, 5H), 4.21 (s, 1H), 3.91 (s, 2H), 3.37-3.28 (m, 2H), 2.90-2.82 (m, 4H), 2.75 (t, J = 6.1, 2H), 1.85-1.78 (m, 1H), 1.77-1.70 (m, 2H), 0.58-0.38 (m, 4H).
EXAMPLE 433 4-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyi}-cyclopropyI-amino)-butyric acid.
A. (2-f4-(Benzoth iazol-2-vloxv)-phenoxv1-ethvlVcvclopro pvl-am i ne. To a stirring 10 solution of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (EXAMPLE 9, 1,1 g, 3.14 mmol) in CH3CN (31 mL) was added cyclopropylamine (1.09 mL, 15,7 mmol) and A/,A/-diisopropylethylamine (1.1 mL, 6.28 mmol). The mixture was heated to 60 °C for 16 h, cooled to room temperature, and then dissolved in CH2Cb (100 mL). The solution was washed with H20 (2 x 20 mL), dried, and 15 concentrated. The resultant oil purified on Si02 (40 g, 0-15% CH3OH/CH2CI2) to give a clear oil (999 mg, 98% yield). MS (ESI): mass calculated for CieH18N202S, 326.11; m/z found, 327.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J = 8.1, 1H), 7.59 (d, J = 8.1, 1H), 7.33 (t, J=8.1, 1H), 7.27-7.17 (m, 3H), 6.95-6,89 (m, 2H), 4.03 (t, J = 5.3, 2H), 3.06 (t, J = 5.3, 2H), 2.20-2^14 (m, 20 1H), 2.02 (bs, 1H), 0.47-0.41 (m, 2H), 0.39-0.34 (m, 2H).
B. 4-({2-F4-fBenzothiazol-2-vloxv1-phenoxv1-ethvl)-cvclopropvi-aminoVbutvric acid ethvl ester. To a stirring solution of {2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyl-amine (950 mg, 2.91 mmol) in CH3CN (29 mL) was added 4-bromo-butyric acid ethyl ester (625 jjJ_, 4.37 mmol) and N,N- diisopropylethylamine (1.0 mL, 5.82 mmol). The mixture was heated to 60 °C for 16 h, cooled to rodm temperature, and then dissolved in CH2CI2(100 mL). The solution was washed with H2O (2 x 20 mL), dried, and concentrated. The resultant oil was purified on SiOz (40 g, 0-50% EtOAc/Hexanes) to give a colorless oil (1.0 g, 78% yield). MS (ESI): mass calculated for C24H28N2O4S, 30 440.18; m/z found, 441.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J= 8.1, 1H), 7.61 (d, J = 8.1, 1H), 7.34 (t, J- 8.1, 1H), 7.28-7.18 (m, 3H), 6.95-6.90 (m, 266 544938 2H), 4.14-4.04 (m, 4H), 3.00 (t, J= 6.3, 2H), 2.71 (t, J= 7.1, 2H), 2.31 (t, J = 7.1, 2H), 1.90-1.80 (m, 3H), 1.23 (t, J = 7.1, 3H), 0.51-0.44 (m, 2H), 0.43-0.38 (m, 2H).
C. 4-({2-f4-fBenzothiazol-2-vloxvVphenoxv1-ethvl>-cvclopropvl-amino)-butvric 5 acid. To a solution of 4-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyf}-cyclopropy!-amino)-butyric acid ethyl ester (970 mg, 2.2 mmol) in 3:1 THF/CH3OH (80 mL), was added lithium hydroxide (211 mg, 8.8 mmol) in water (20 mL). This solution was stirred at room temperature for 16 h and then adjusted the pH to 7 using 1 N aqueous HCI. Extracted the mixture with CH2CI2 10 (2 x 100 mL). The combined organic phase was concentrated under reduced pressure. The resultant oil was purified on Si02 (40 g, 0-10% CH3OH/CH2CI2) to give a white solid (877 mg, 97% yield). MS (ESI): mass calculated for C22H24N2O4S, 412.15; m/z found, 413.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 11.44 (brs, 1H), 7.68 (d, J = 8.1, 1H), 7.62 (d, J = 8.1, 1H),7.35 (t, J = 8.1, 15 1H), 7.27-7.20 (m, 3H), 7.01-6.95 (m, 2H), 4.44 (t, J = 5.0, 2H), 3.56 (t, J = 5.005, 2H), 3.32 (t, J- 8.1, 2H), 2.67-2.60 (m, 1H), 2.46 EXAMPLE 434 1-{3-[4-(Benzothiazo!-2-yloxy)-benzylamino]-propyl}-pyrroiidin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 251, step B using 1-(3-amino-propyl)-pyrrolidine-2-one. MS (ESI): mass 25 calculated for C21H23N3O2S, 381.15; m/z found, 382.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J = 8.1, 1H), 7.64 (d, J = 8.1, 1H), 7.45-7.41 (m, 2H), 7.36 (t, J- 8.1, 1H), 7.32-7.28 (m, 2H), 7,24 (t, J = 8.1, 1H), 3.81 (s, 2H), 3.38-3.27 (m, 5H), 3.63 (t, J= 6,8, 2H), 3.35 (t, J= 7.6, 2H), 2.02-1.93 (m, 2H), 1.82-1.73 (m, 2H).
O 267 544938 EXAMPLE 435 O 1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-methyl-amino}-propyI)-pyrroIidin-2-one.
The title compound was prepared according to the procedure for EXAMPLE 409 using formaldehyde. MS (ESI); mass calculated for C22H25N3O2S, 395,17; m/z found, 396.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J- 8,1, 1H), 7.64 (d, J = 8.1, 1H), 7.43-7.27 (m, 5H), 7.24 (t, J = 8.1, 1H), 3,54 (s, 2H), 3.32 (dd, J= 7.1, 7.1, 4H), 2.43 (t, J= 7.1, 2H), 2.34 (t, J = 7.1, 2H), 2.23 (s, 3H), 10 2.00-1.91 (m, 2H), 1.80-1.70 (m, 2H).
EXAMPLE 436 O 1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-isopropy!-amino}-propyl)-pyrro!idin-2-15 one.
The title compound was prepared according to the procedure for EXAMPLE 409 using acetone. MS (ESI); mass calculated for C24H29N3O2S, 423.20; m/z found, 424.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7,72 (d, J = 8.1, 1H), 7.65 20 (d, J = 8.1, 1H), 7.45-7.40 (m, 2H), 7.37 (t, J = 7,8, 1H), 7.30-7.21 (m, 3H), 3.55 (s, 2H), 3.29-3.20 (m, 4H), 3.01,2.90 (m, 1H), 2.42 (t, J = 7.1, 2H), 2.32 (t, J = 7.8, 2H), 1.97-1.83 (m, 2H), 1.63-1.53 (m, 2H), 1.02 (d, J = 6.6, 6H), EXAMPLE 437 0 1-(3-{[4-(Benzothiazol-2-yloxy)-benzyI]-ethyi-amino}-propyl)-pyrrolidin-2-one. 268 544938 The title compound was prepared according to the procedure for EXAMPLE 409 using acetaldehyde. MS (ESi): mass calculated for C23H27N302St 409.18; m/z found, 410.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 5 7.66 (d, J = 8.1, 1H), 7.43-7.34 (m, 3H), 7.32-7.23 (m, 3H), 3.56 (s, 2H), 3.30 (dd, J- 7.1, 7.1, 4H), 2.53 (dd, J = 7.1, 7.1, 2H), 2.45 (t, J = 7.1, 2H)( 2.34 (t, J = 7.8, 2H), 2.00-1.91 (m, 2H), 1.73-1.64 (m, 2H), 1.04 (t, J = 7.1, 3H).
EXAMPLE 438 [4-(Benzothiazol-2-yloxy)-benzyl]-cycIopropyl-amine, The title compound was prepared according to the procedure for EXAMPLE 251, step B using cyciopropylamine. MS (ESI): mass calculated for 15 Ci7H16N2OS, 296.10; m/z found, 297.3 [M+Hf. 1H NMR (400 MHz, GDCI3): 7.72 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.40-7.33 (m, 3H), 7.32-7.27 (m, 2H), 7.24 (t, J = 8.1, 1H), 3.85 (s, 2H), 2.19-2.12 (m, 1H), 1.86 (brs, 1H), 0.48-0.35 (m, 4H).
EXAMPLE 439 N-1 -[4-(Benzothiazoi-2-yloxy)-benzyl]-N1 -cyclopropyl-propane-1,3-diamine. The title compound was prepared according to the procedure for EXAMPLE 421 using compound from EXAMPLE 438. MS (ESI): mass calculated for C20H23N3OS, 353.16; m/z found, 354.3 [M+Hf. 1H NMR (400 MHz, CDC13): 7.73 (d, J = 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.41-7.32 (m, 3H), 7.30-7.23 (m, 3H), 3.75 (s, 2H), 2.67 (t, J - 7.1, 2H), 2.58 (t, J= 7.1, 2H), 1.80-1.73 (m, 1H), 1.72-1.64 (m, 2H), 1.19 (brs, 2H), 0.52-0.46 (m, 2H), 0.42-0.36 (m, 2H). 269 !) »,„r " ■ 544938 EXAMPLE 440 N-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyi-amino}-propyi)-5 isobutyramide.
The title compound was prepared according to the procedure for EXAMPLE 422 using isobutyryl chloride. MS (ESI): mass calculated for C24H29N302S, 423.20; m/z found, 424.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 10 1H), 7.65 (d, J = 8.1, 1H), 7.40-7.22 (m, 6H), 6.26 (brs, 1H), 3.73 (s, 2H), 3.23 (dd, J = 6.3, 5.8, 2H), 2.61 (t, J = 6.6, 2H), 2,29-2.18 (m, 1H), 1.79-1.68 (m, 3H), 1.09 (d, J = 6.8, 6H), 0.54-0.47 (m, 2H), 0.43-0.37 (m, 2H).
EXAMPLE 441 1-(3-{[4-(Benzothiazol-2-yloxy)-benzyi3-cyciopropy!-amino}-propyI)-3-iso|sropyi-urea.
The title compound was prepared according to the procedure for EXAMPLE 20 422 using isopropyl isocyanate. MS (ESi): mass calculated for C24H30N4O2S, 438.21; m/z found, 439.4 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.69 (d, J = 8.1, 1H), 7.63 (d, J= 8.1, 1H), 7.38-7.29 (m, 3H), 7.27-7.20 (m, 3H), 5.44 (brs, 1H), 5.15 (d, J = 7.8, 1H), 3.87-3.76 (m, 1H), 3.70 (s, 2H), 3.12 (dd, J = 6.3, 6.1, 2H), 2.56 (t, J = 7.1, 2H), 1.76-1.67 (m, 3H), 1.07 (d, J = 6.3, 6H), 0.49-0.42 (m, 25 2H), 0.40-0.34 (m, 2H). 270 544938 EXAMPLE 442 H H OiriXOTr 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-isopropyI-urea, The title compound was prepared according to the procedure for EXAMPLE 253, step C using isopropyl isocyanate. MS (ESI); mass calculated for C23H28N4O2S, 424.19; m/z found, 425.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.67 (d, J = 8.1, 1H), 7.41-7.35 (m, 3H), 7.32-7.24 (m, 3H), 4.77 (dd, J= 8.1, 7.8, 1H), 3.88-3.78 (m, 1H), 3.66-3.55 (m, 1H), 3.51 (s, 10 2H), 2.82 (d, J = 11.6, 2H), 2.13 (t, J = 10.9, 2H), 1.94 (d, J = 11.9, 2H), 1.69 (brs, 1H), 1.48-1.36 (m, 2H), 1.14 (d, J = 6.6, 6H).
EXAMPLE 443 N-{1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-oxaiamic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using chloro-oxo-acetic acid methyl ester. MS (ESi): mass 20 calculated for C22H23N3O4S, 425.14; m/z found, 426.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.78 (d, 8.1, 1H), 7.64 (d, J= 8.1, 1H), 7.55-7.50 (m, 2H), 7.44-7.36 (m, 3H), 7.31 (t, J = 8.1, 1H), 3.84 (s, 2H), 3.81-3.72 (m, 1H), 3.41 (s, 3H), 3.11 (d, J= 10.9, 2H), 2.59-2.47 (m, 2H), 2.00-1.91 (m, 2H), 1.79-1.66 (m, 2H). 271 544938 EXAMPLE 444 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-isobutyramide.
The title compound was prepared according to the procedure for EXAMPLE 253 using isobutyryl chloride. MS (ESI): mass calculated for C23H27N3O2S, 409.18; m/z found, 410.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.84 (d, J = 8.6, 2H), 7.69 (t, J = 7.8, 2H), 7.44 (d, J = 8.6, 2H), 7.41-7.33 (m, 2H), 7.27 (t, J = 8.1, 1H), 4.33 (s, 2H), 4.16-4.00 (m, 1H), 3.57-3.42 (m, 2H), 3.31-3.16 (m, 2H), 10 2.58-2.45 (m, 1H), 2.31-2.07 (m, 4H), 1.10 (d, J = 6.8, 6H).
EXAMPLE 445 Tetrahydro-furan-2-carboxylic acid {1 -[4-(benzothiazol-2-yloxy)-benzyl]-15 piperidin-4-yl}-amide.
The title compound was prepared from EXAMPLE 253, step D followingythe procedure for EXAMPLE 431. MS (ESI): mass calculated for C24H27N3O3S, 437.18; m/z found, 438.3 [M+H]+. 1H NMR (400 MHz, CDCI3): 11.03 (brs, 20 1H), 7.73 (d, J = 7.8, 1H), 7.67 (d, J = 7.8, 1H), 7.46-7.42 (m, 2H), 7.41-7.32 (m, 3H), 7.27 (d, J = 7.8, 1H), 4.31 (t, J = 8.34, 1H), 3.98-3.89 (m, 1H), 3.84 (s, 2H), 3.19 (d, J= 11.6, 2H), 2.43 (t, 10.4, 2H), 2.34-2.21 (m, 2H), 2.08-1.69 (m, 8H).
EXAMPLE 446 ,xOH 272 544938 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-4-hydroxy-pyrrolidin-2- The title compound was prepared from EXAMPLE 253, step D following the 5 procedure for EXAMPLE 254, step D. MS (ESI): mass calculated for CaaHasNaOaS, 423.16; m/z found, 424.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 7.80 (d, J = 8.1, 1H), 7.68-7.62 (m, 3H), 7.53-7.49 (m, 2H), 7.42 (t, J = 8.1, 1H), 7.32 (t, J= 8.3, 1H), 4.44 (t, J = 6.3, 1H)t 4.38 (s, 2H), 4.25-4.15 (m, 1H), 3.68-3.57 (m, 3H), 3.33-3.13 (m, 3H), 2.71 (dd, J = 10.9, 6.3, 1H), 2.28 (t, J = 17.7, 10 1H), 2.13-2.02 (m, 2H), 2.01-1.92 (m, 2H).
EXAMPLE 447 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yI}-4-hydroxy-pyrroiidin-2-15 one.
The title compound was prepared from EXAMPLE 253, step D following the procedure for EXAMPLE 254, step D. MS (ESI): mass calculated for C23H25N3O3S, 423.16; m/z found, 424.3 [M+Hf. 1H NMR (400 MHz, CD3OD): 20 7.80 (d, J = 8.1, 1H), 7.68-7.62 (m, 3H), 7.53-7.49 (m, 2H), 7.42 (t, J = 8.1, 1H), 7.32 (t, J = 8.3, 1H), 4.44 (t, J - 6.3, 1H), 4.38 (s, 2H), 4.25-4.15 (m, 1H), 3.68-3.57 (m, 3H), 3.33-3.13 (m, 3H), 2.71 (dd, J = 10.9, 6.3, 1H), 2.28 (t, J = 17.7, 1H), 2.13-2.02 (m, 2H), 2.01-1.92 (m, 2H).
EXAMPLE 448 one.
H {1-[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl}-urea, 273 544938 The title compound was prepared according to the procedure for EXAMPLE 253, step C using trimethylsilyl isocyanate. MS (ESI); mass calculated for C20H22N4O2S( 382.15; m/z found, 383.3 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.71 (d, J = 7.8, 1H), 7.63 (d, J= 7.8, 1H), 7.40-7.33 {m, 3H), 7.30-7.21 (m, 5 3H), 5.82 (d, J = 7.8, 1H), 5.10 (d, J = 4.6, 1H), 3.84 (s, 1H), 3.56 (br s, 1H), 3.49 (s, 2H), 2.81 (d ,J= 11.6, 2H), 2.12 (t, J= 11.1, 2H), 1.90 (d, J = 11.9, 2H), 1.51-1.39 (m, 2H).
EXAMPLE 449 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxalamic acid.
The title compound was prepared from EXAMPLE 443 following the procedure for EXAMPLE 433, step C. MS (ESI): mass calculated for C2iH21N304S, 15 411.13; m/z found, 412.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.78 (d, J = 8.1, 1H), 7.64 (d, J= 8.1, 1H), 7.55-7.50 (m, 2H)t 7.44-7.36 (m, 3H), 7,31 (t, J = 8.1, 1H), 3.84 (s, 2H), 3.81-3.72 (m, 1H), 3.11 (d, J= 10.9, 2H), 2.59-2.47 (m, 2H), 2.00-1.91 (m, 2H), 1.79-1.66 (m, 2H).
/ EXAMPLE 450 H N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-2-hydroxy-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 25 431 using glycolic acid. MS (ESI): mass calculated for C21H23N3O3S, 397.15; m/z found, 398.3 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.71 (d, J = 7.8, 1H), 7.65 (d, J = 8.1, 1H), 7.40-7.35 (m, 3H), 7.31-7.23 (m, 3H), 6.83 (d, J = 8.1, 274 544938 1H), 5.33, (brs, 1H), 3.99 (s, 2H), 3.87-3.75 (m, 1H), 3.50 (s, 2H), 2.85 (d, J = 11.4, 2H), 2.14 (t, J= 10.9, 2H), 1.92 (d, J = 12.6, 2H), 1.56-1.43 (m, 2H).
EXAMPLE 451 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-2,2,2-trifluoro-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 431 using trifluoroacetic acid. MS (ESI): mass calculated for C21H20F3N3O2S, 10 435.12; m/z found, 436.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J = 8.3, 2H), 7.54 (d, J= 8.6, 2H), 7.47 (d, J= 8.8, 2H), 7.41 (t, J = 8.3, 1H), 7.34-7.28 (m, 1H), 4.24 (s, 2H), 4.15-4.02 (m, 1H), 3.59 (d, J= 12.1, 2H), 3.40, (brs, 1H), 2.87 (t, J = 11.9, 2H), 2.22-2.02 (m, 4H).
EXAMPLE 452 2-[4-(1,1 -Dioxo-1 l6-thiomorpholin-4-ylmethyI)-phenoxy]-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 20 251 using thiomorpholine -1,1-dioxide. MS (ESI): mass calculated for C18Hi8N203S2, 374.08; m/z found, 375.2 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1,1 H), 7.67 (d, J = 8.1, 1H), 7.42-7.31 (m, 5H), 7.27 (tT J = 7.8, 1H), 3.66 (s, 2H), 3.03 (d, J = 26.3, 8H).
EXAMPLE 453 O H H 275 544938 N-{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4--amino sulfonyl}-carbamic acid tert-butyl ester The title compound was prepared according to the procedure for EXAMPLE 5 253 using carbamic acid, N-(sulfonyl chloride) tert butyl ester. MS (ESI): mass calculated for C24H30N4O5S2, 518.17; m/z found, 519.5 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.2, 1H), 7.67 (d, J- 8.2, 1H), 7.42-7.35 (m, 3H), 7.34-7.24 (m, 3H), 5.18 (brs, 1H), 3.55 (s, 2H), 3.39-3.29 (mf 1H), 2.83 (d, J = 11.7, 2H), 2.31-2.18 (m, 2H), 1.98 (d, J= 11.7, 2H), 1.72-1.59 (m, 2H), 1.47 (s, 10 9H).
EXAMPLE 454 H N~{1-[4-(Benzothiazol-2-yloxy)-benzyl]~piperidin-4-yi}-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using acetyl chloride. MS (ESI): mass calculated for C21H23N302S, 381.15; m/z found, 382.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 7.8, 1H), 7.67 (d, J = 8.1, 1H), 7.43-7.36 (m, 3H), 7.33-7.24fm, 20 3H), 5.65 (br s, 1H), 3.87-3.76 (m, 1H), 3.54 (s, 2H), 2.86 (d, J - 12.1, 2H), 2.17 (t, J = 11.4, 2H), 1.97 (s, 3H), 1.93 (d, J = 11.9, 2H), 1.56-1.44 (m, 2H).
EXAMPLE 455 OXCuCr^ N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-NsN-dimethylsulfamide The title compound was prepared according to the procedure for EXAMPLE 253, step C using N,N-dimethyl-su!famoyi chloride. MS (ESI): mass calculated 276 544938 for C21H26N4O3S2, 446.14; m/z found, 447.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7.41-7.35 (m, 3H), 7.32-7.23 (m, 3H), 4.37 (d, J = 7.8, 1H),3.49(s, 2H), 3.28-3.17 (m, 1H), 2.81 (d, J-10.9, 2H), 2.78 (s, 6H), 2.11 (t, J= 11.1, 2H), 1.98 (d, J= 10.9, 2H), 1.61-1.50 5 (m, 2H).
EXAMPLE 456 H H 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-ethyi-urea.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using ethyl isocyanate. MS (ESI): mass calculated for C22H26N4O2S, 410.18; m/z found, 411.5 [M+H]+, 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.66 (d, J= 8.1, 1H), 7.42-7.34 (m, 3H), 7.32-7.23 (m, 15 3H), 4.54 (br s, 1H), 4.45 (d, J = 7.6, 1H), 3.67-3.55 (m, 1H), 3.50 (s, 2H), 3.23-3.14 (m, 2H), 2.80 (d, J = 11.9, 2H), 2.13 (t, J= 11.4, 2H), 1.93 (d, J = 12.6, 2H), 1.48-1.36 (m, 2H), 1.12 (t, J = 7.3, 3H).
EXAMPLE 457 H H 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin~4-yl}-3-ethyi-thiourea.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using ethyl isothiocyanate. MS (ESI): mass calculated for 25 C22H26N4OS2, 426.15; m/z found, 427.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.71 (d, J = 7.8, 1H), 7.67 (d, J = 8.1, 1H), 7.41-7.34 (m, 3H), 7.32-7.24 (m, 3H), 6.03 (brs, 1H), 5.74 (brs, 1H), 4.20-4.00 (m, 1H), 3.51 (s, 2H), 3.47-3.35 277 544938 (m, 2H), 2.82 (d, J = 11.6, 2H), 2.05 (t, J = 11.1, 2H), 2.05 (d, J = 11.9, 2H), 1.57-1.45 (m, 2H), 1.21 (t, J = 7.3, 3H).
EXAMPLE 458 Propane-1 -sulfonic acid {1-[4-(benzothiazoI-2-yioxy)-benzyl]-piperidin-4-yl}-amide.
The title compound was prepared according to the procedure for EXAMPLE 10 253, step C using 1-propanesulfonyl chloride. MS (ESI): mass calculated for C22H27N3O3S2, 445.15; m/z found, 446.4 [M+Hf, 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.40-7.34 (m, 3H), 7.32-7.22 (m, 3H), 4.85 (d, J = 8.1, 1H), 3.48 (s, 2H), 3.36-3.24 (m, 1H), 3.02-2.94 (m, 2H), 2.81 (d, J = 11.9, 2H), 2.11 (t, J = 10.6, 2H), 1.95 (d, J = 12.6, 2H), 1.89-1.78 15 (m, 2H), 1.65-1.54 (m, 2H), 1.04 (t, J = 7.3, 3H).
EXAMPLE 459 Propane-2-sulfonic acid {1 -[4-{benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-20 amide.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using 2-propanesulfonyl chloride. MS (ESI): mass calculated for C22H27N3O3S2, 445.15; m/z found, 446.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 25 7.73 (d, J = 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7,41-7.35 (m, 3H), 7,32-7.24 (m, 3H), 3.79 (d, J= 5.6, 1H), 3.51 (s, 2H), 3.38-3.27 (m, 1H), 2.89-2.78 (m, 2H), 2.19-1.94 (m, 5H), 1.76 (d, J = 30.8, 6H), 1.69-1.55 (m, 2H).
H / 278 544938 EXAMPLE 460 CcTCuCr^ N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-sulfamide The title compound was prepared from EXAMPLE 453 following the procedure for EXAMPLE 253, step B. MS (ESi): mass calculated for Cigh^^OsSa, 418.11; m/z found, 419.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 10.68 (br s, 1H), 7.60 (d, J = 8.3, 1H), 7.56 (d, J = 8.3, 1H), 7.48-7.38 (m, 2H), 7.32-7.24 (m, 3H), 7.18 (t, J = 7.8,1H), 6.24 (br s, 2H), 4.10 EXAMPLE 461 H N-{1-[4-(Benzothiazo!-2-yioxy)-benzyi]-piperidin-4-yl}-formamide, The title compound was prepared according to the procedure for EXAMPLE 431, formic acid. MS (ESi): mass calculated for C2oH2iN302S, 367.14; m/z found, 368.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 12.28 (br s, 1H), 7.73 (d,J = 7.8, 1H), 7.68, (d, J = 7.8,1 H), 7.47-7.24 (m, 6H), 6.33 (d, J = 7.3, 1H), 4.05-20 3.94 (m, 1H), 3.80 (s, 2H), 3.14 (d, J= 11.6, 2H), 2.41 (t, J= 11.9, 2H), 1.99 (d, J- 13.1, 2H), 1.83-1.70 (m, 2H).
EXAMPLE 462 axxxxfT" {1 -[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid ethyl ester. 279 544938 The title compound was prepared according to the procedure for EXAMPLE 253, step C using ethyl chloroformate. MS (ESI): mass calculated for C22H25N3O3S, 411.16; m/z found, 412.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1,1 H), 7.66 (d, J = 8.1, 1H), 7.41-7.34 (m, 3H), 7.32-7.22 (m, 5 3H), 4.62 (brs, 1H),4.10 (dd, J= 7.3, 6.8, 2H), 3.59-3.51 (m, 1H), 3.49 (s, 2H), 2.80 (d, J = 11.6, 2H), 2.12 (t, J = 11.6, 2H), 1.93 (d, J = 12.1, 2H), 1.51-1.39 (m, 2H), 1.23 (t, J = 7.1, 3H).
EXAMPLE 463 H |\j-{i-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-propionamide, The title compound was prepared according to the procedure for EXAMPLE 253, step C using propionyl chloride, MS (ESI): mass calculated for 15 C22H25N3O2S, 395.17; m/z found, 396.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.41-7.34 (m, 3H), 7.32-7.22 (m, 3H), 5.61 (d, J= 8.1, 1H), 3.87-3.76 (m, 1H), 3.49 (s, 2H), 2.82 (d, J=11.9, 2H), 2.22-2.07 (m, 4H), 1.90 (d, J= 13.1, 2H), 1.51-1.39 (m, 2H), 1.14 (t, J = 7.6, 3H). f EXAMPLE 464 H N-{1-I4-(BenzothiazoI-2-yloxy)-benzyl]-piperidin-4-yl}-butyramide.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using butyryl chloride. MS (ESI): mass calculated for C23H27N3O2S, 409.18; m/z found, 410.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.40-7.35 (m, 3H), 7.31-7.23 (m, 3H), 5.64 (d, J = 8.1, 1H), 3.87-3.77 (m, 1H),3.49 (s, 2H), 2.81 (d, J=11.6, 280 544938 2H), 2.16-2.07 (m,4H), 1.91 (d, J=12.9, 2H), 1.71-1.60 (m, 2H), 1.51-1.39 (m, 2H), 0.93 (t, J=7.3,3H).
EXAMPLE 465 H H 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-y!}-3-propyl-urea.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using propyl isocyanate. MS (ESi): mass calculated for 10 C23H28N4O2S, 424.19; m/z found, 425.5 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.70 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.39-7.33 (m, 3H), 7.28-7.21 (m, 3H), 5.54 (brs, 1H), 5.37 (d, J = 8.1, 1H), 3.66-3.56 (m, 1H), 3.48 (s, 2H), 3.11 (dd, J = 7.1, 6.8, 2H), 2.80 (d, J = 11.1, 2H), 2.11 (t, J = 11.1, 2H), 1.91 (d, J = 11.1, 2H), 1.54-1.38 (m, 4H), 0.91 (t, J = 7.3, 3H).
EXAMPLE 466 H {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid propyl ester.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using propyl chloroformate. MS (ESI): mass calculated for C23H27N3O3S, 425.18; m/z found, 426.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.39-7.33 (m, 3H), 7.31-7.21 (m, 3H), 4.83 (d, J = 7.6, 1H), 4.00 (t, J = 6.6, 2H), 3.58-3.49 (m, 1H), 3.47 (s, 2H), 25 2.79 (d, J= 11.6, 2H), 2.10 (t, J = 10.9, 2H), 1.91 (d, J = 11.1, 2H), 1.67-1.56 (m, 2H), 1.52-1.40 (m, 2H), 0.92 (t, J= 7.6, 3H). 281 544938 EXAMPLE 467 H H 1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-methyl-urea.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using methyl isocyanate. MS (ESI): mass calculated for C21H24N4O2S, 396.16; m/z found, 397.4 [M+H]+. 1H NMR (400 MHz, CDC!3): 7.71 (d, J = 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.45-7.34 (m, 3H), 7.33-7.22 (m, 3H), 5.71 (brs, 2H), 3.69-3.59 (m, 1H), 3.56 (s, 2H), 2.87 (d, J= 11,9, 2H), 10 2.73 (d, J = 4.8, 3H), 2.21 (t, J= 10.1, 2H), 1.93 (d, J = 10.4, 2H), 1.58-1.45 (m, 2H).
EXAMPLE 469 I H 1-{1 -[4-(Benzothiazol~2-yloxy)-benzyl]-piperidin-4-yI}-1,3-dimethyl-urea.
The title compound was prepared according to the procedure for EXAMPLE 255, step C using methyl isocyanate. MS (ESI); mass calculated for C22H26N4O2S, 410.18; m/z found, 411.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 20 7.72 (d, J = 8.1, 1H), 7.65 (d, J = 8.1, 1H)f 7.41-7.34 (m, 3H), 7.31-7.22 (m, 3H), 4.63 (dd, J = 4.6, 4.6, 1H), 4.21-4.11 (m, 1H), 3.49 (s, 2H), 2,93 (d, J = 11.9, 2H), 2.79 (d, J = 4.8, 3H), 2.71 (s, 3H), 2.08 (t, J = 11.9, 2H), 1.76-1.64 (m, 2H), 1.63-1.54 (m, 2H).
EXAMPLE 470 282 544938 1-{1 -[4-(Benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl}-1 -methyl-urea.
The title compound was prepared according to the procedure for EXAMPLE 255, step C using trimethylsilyi isocyanate, MS (ESI): mass calculated for 5 C21H24N4O2S, 396.16; m/z found, 397.4 [M+Hf. 1H NMR (400 MHz, CDCl3): 7.72 (d, J = 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.42-7.34 (m, 3H), 7.32-7.21 (m, 3H), 4.93 (s, 2H), 4.16-4.03 (m, 1H), 3.50 (s, 2H), 2.94 (d, J- 11.4, 2H), 2.76 (s, 3H), 2.09 (t, J = 11.4, 2H), 1.79-1.66 (m, 2H), 1.65-1.56 (m, 2H).
EXAMPLE 471 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-acetamide.
The title compound was prepared according to the procedure for EXAMPLE 15 255, step C using acetyl chloride. MS (ESI): mass calculated for C22H25N3O2S, 395.17; m/z found, 396.4 [M+Hf, 1H NMR (400 MHz, CDCI3): 7.72 (d, J - 8.1, 1H), 7.65 (d, J = 8.1, 1H), 7.41-7,34 (m, 3H), 7.31-7.22 (m, 3H), 4.55-4.44 (m, 1H), 3.49 (s, 2H), 3.01-2.90 (m, 2H), 2.84 (s, 3H), 2.15-2.09 (m, 2H), 2.07 (s, 3H), 1.77-1.65 (m, 2H), 1.64-1.53 (m, 2H).
EXAMPLE 472 {1 -[4-(Benzothiazoi-2-yloxy)-benzyl]-piperidin-4-yl}-methy!-carbamic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 255, step C using methyl chloroformate. MS (ESI): mass calculated for C2iH25N303S, 411.16; m/z found, 412.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 283 544938 7.73 (d, J = 8.1, 1H), 7.66 (d, J = 8.1, 1H), 7.42-7.35 (m, 3H), 7.33-7.24 (m, 3H), 4.16-3.96 (m, 1H), 3.69 (s, 3H), 3.51 (s, 2H), 2.95 (d,J= 11.4, 2H), 2.78 (s, 3H), 2.08 (t, J= 10.9, 2H), 1.82-1.69 (m, 2H), 1.65-1.57 {m, 2H).
EXAMPLE 473 N-{l-[4-(Benzothiazol-2-yIoxy)-benzyl]-piperidin-4-yl}-N-methyl-oxalamic acid methyl ester.
The title compound was prepared according to the procedure for EXAMPLE 255, step C using chloro-oxo-acetic acid methyl ester. MS (ESI): mass calculated for C23H25N3O4S, 439.16; m/z found, 440.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.73 (d, J = 8.1, 1H), 7.66 (d, 8.1, 1H), 7.41-7.34 (m, 3H), 7.33-7.23 (m, 3H), 4.41-4.32 (m, 1H), 3.87 (s, 3H), 3.51 (s, 2H), 2.97 (d, J = 15 11.9, 2H), 2.88 (s, 3H), 2.13 (t, J= 11.9, 2H), 1.95-1.83 (m, 2H), 1.72-1.62 (m, 2H).
EXAMPLE 474 N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methy!-oxalamicacid.
The title compound was prepared from EXAMPLE 473 following the procedure for EXAMPLE 433, step C. MS (ESI); mass calculated for C22H23N3O4S, 425.14; m/z found, 426.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7,68 (d, J= 8.1, 25 1H), 7.59 (d, J = 8.1, 1H), 7.37-7.28 (m, 3H), 7.27-7.16 (m, 3H), 4.27-4.16 (m, 1H), 3.43 (s, 2H), 2.93 (d, J = 11.897, 2H), 2.75 (s, 3H), 2.01 (t, J - 11.9, 2H), 1.82-1.65 (m, 2H), 1.58-1.47 (m, 2H). o 284 544938 EXAMPLE 475 0fiftXGX Guanidine, N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N'-hydroxy A. 1-r4-(Benzothiazol-2-vloxvVbenzvl1-piperidin-4-vi-cvanamide. To a suspension of 1-[4-(benzothiazol-2-yloxy)-benzyI]-piperidin-4-ylamine (339 mg, 1.0 mmol) in CH3OH (2.0 mL) was added sodium acetate (180 mg, 2.2 mmol) at room temperature. The suspension became a clear solution. Cooled the solution to 0 °C. Cyanogen bromide (159 mg, 1.5 mmol) in CH3OH (0.7 mL) 10 was added dropwise. The reaction mixture was stirred at 5 °C for 2 h and then at ambient temperature overnight. The mixture was filtered through a frit fnnei and the filtrate was absorbed onto silica gel (40 g) and purified (0-10% CH30H/CH2C[2) to give an unstable oil (123 mg, 34% yield). MS (ESI): mass calculated for C20H20N4OS, 364.14; m/z found, 365.3 [M+H]+, 15 B. Guanidine. N-f 1 -r4-fBenzothiazo[-2-vloxvVbenzvll-piperidin-4-vl)-N'-hvdroxv. To a solution of 1-[4-(benzothiazol-2-yloxy)-benzyI]-piperidin-4-yl-cyanamide (123 mg, 0.34 mmol) in DMF (2 mL) was added hydroxylamine hydrochloride (41.5 mg, 0.60 mmol), followed by sodium carbonate (119 mg, 1,12 mmol) in small portions. The reaction mixture was stirred at room temerature for 2 h and 20 partitioned between EtOAc (20 mL) and H20 (20 mL). The organic phase was washed with brine, dried and concentrated under reduced pressure to yield the crude product as a pale solid. The crude product was purified on Si02 (12 g; 0-10% CH3OH/CH2CI2) to give a white soid (117 mg, 86% yield). MS (ESI): mass calculated for C2oH23N504S, 397.16; m/z found, 398.4 [M+Hf. 1H NMR (400 25 MHz, CDCI3): 7.71 (d, J = 8.1, 1H), 7.63 (d, J = 8,1, 1H), 7.38-7.32 (m, 3H), 7.28-7.21 (m, 3H), 4.69 (br s, 2H), 3.46 (s, 2H), 3.27-3.16 (m, 1H), 2.78 (d, J = 10.9, 2H), 2.04 (t, J = 11.1, 2H), 1.92 (d, J = 11.1, 2H), 1.51-1.38 (m, 2H). 285 544938 EXAMPLE 476 H CcTTXCrVr {1 -[4-(Benzothiazol-2-yioxy)-benzyI]-piperidin-4-yl}-carbamic acid isopropyl ester.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using isopropyl isocyanate. MS (ESI): mass calculated for C23H27N3O3S, 425.18; m/z found, 426.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 8.1, 1H), 7.63 (d, J = 8.1, 1H), 7.38-7.33 (m, 3H), 7.31-7.21 (m, 10 3H), 4.95-4.85 (m, 1H), 4.75 (d, J = 7.1, 1H), 3.58-3.49 (m, 1H), 3.47 (s, 2H), 2.79 (d, J = 11.6, 2H), 2.09 (t, J = 11.4, 2H), 1.91 (d, J = 11.9, 2H), 1.50-1.39 (m, 2H), 1.21 (d, J= 6.5, 6H).
EXAMPLE 477 3_{1 -[4-(BenzothiazoI-2-yloxy)-benzyl]-piperidin-4-yl}-1,1 -dimethyl-urea.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using N,N~dimethylcarbamoy! chloride. MS (ESI): mass calculated 20 for C22H26N4O2S, 410.18; m/z found, 411.4 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.71 (d, J= 8.1, 1H), 7.64 (d, J = 8.1, 1H), 7.39-7.33 (m, 3H), 7.30-7.21 (m, 3H), 4.41 (d, J = 7.8, 1H), 3.73-3.62 (m, 1H), 3.48 (s, 2H), 2.87 (s, 6H), 2.81 (d, J= 11.6, 2H), 2.11 (t, J=11.9, 2H), 1.93 (d,J=11.6, 2H), 1.50-1.38 (m,2H).
H [ 286 544938 EXAMPLE 478 Acetic acid {1 -[4-(benzothiazol-2-yloxy)-benzyI]-piperidin-4-yIcarbamoyI}~methyI ester.
The title compound was prepared according to the procedure for EXAMPLE 253, step C using acetic acid chlorocarbonyl methyl ester. MS (ESI): mass calculated for C23H25N3O4S, 439.16; m/z found, 440.4 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J = 7.8, 1H), 7.65 (d, J = 8.1, 1H), 7.40-7.35 (m, 3H), 10 7.32-7.23 (m, 3H), 6.11 (d, J = 8.3, 1H), 4.53, (s, 2H), 3.93-3.82 (m, 1H), 3.50 (s, 2H), 2.83 (d, J - 11.9, 2HJ, 2.15 (s, 3H), 2.14 (t, J = 11.9, 2H), 1.93 (d, J = 12.1, 2H), 1.56-1.45 (m, 2H).
EXAMPLE 479 H ^.N^NH2 N^J S {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yi}-thiourea.
A. l-(l-f4-fBenzothiazol-2-vloxvVbenzvl1-piperidin-4-vl>-3-benzovl-thiourea. The title compound was prepared according to the procedure for EXAMPLE 253, step C using benzoyl isocyanate. MS (ESI): mass calculated for C27H26N402S2, 502.15; m/z found, 503.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 10.80 (d, J = 8.1, 1H), 9.06 (s, 1H), 7.81 (d, J = 8.3, 2H), 7.72 (d, J = 8.3, 1H), 7.65 (d, J = 7.8, 1H), 7.59 (t, J = 7.6, 1H), 7.50-7.45 (m, 2H), 7.42-7.34 (m, 3H), 7.33-7.22 (m, 3H), 4.40-4.29 (m, 1H), 3.53 (s, 2H), 2.80 (d, J = 11.1, 2H), 2.26 25 (t, J = 10.1, 2H), 2.12 (d, J = 11.9, 2H), 1.76-1.64 (m, 2H).
B. f1-r4-fBenzothiazol-2-vloxvVbenzvn-piperidin-4-vlMhiourea. To 1-{1-[4- (benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-benzoyl-thiourea (300 mg, 0.60 mmol) was added 10% aqueous sodium hydroxide (10 mL). The reaction mixture was heated at reflux for 1 h. The resulting white suspension was 287 1 K 544938 cooled to room temperature and extracted with 10% CH3OH/CH2CI2 (3 x 50 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure to yield the crude product as an off-white solid. The crude product was purified on Si02 (40 g; 0-10% CH3OH/CH2CI2) to give the title compound 5 as a white solid (219 mg, 92% yield). MS (ESI): mass calculated for C2oH22N40S2j 398.12; m/z found, 399.3 [M+Hf. 1H NMR (400 MHz, CDCI3): 7.72 (d, J= 8.1, 1H), 7.68 (d, J= 8.1, 1H), 7.42-7.36 (m, 3H), 7.34-7.26 (m, 3H), 6.09 (m, 1H), 4.29-4.02 (m, 1H), 3.57 (s, 2H), 2.88 (d, J = 11.1, 2H), 2.29 (s, 2H), 2.20 (t, J- 11.1, 2H), 2.04 (d, J= 10.1, 2H), 1.60-1.45 (m, 2H).
EXAMPLE 480 (1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-methanol, The title compound was prepared according to the procedure for EXAMPLE 37, using piperidin-4-yl-methanol. MS (ESI): mass calculated for C21H25N3O3, 367.19; m/z found, 368.4 [M+Hf. 1H NMR (400 MHz, DMSO-d6): 12.24 (s, 1H), 7.32 (s, 2H), 7.27 (d, J = 8.9, 2H), 7.08 (s, 2H), 7.00 (d, J = 8.9, 2H), 4.41 (s, 1H), 4.09 (s, 2H), 3.24 (s, 2H), 2.92 (d, J = 11.1, 2H), 2.68 (s, 2H), 1&8 (t, J 20 =11.6, 2H), 1.62 (d, J = 11.6, 2H), 1.24 (br s, 1H), 1.11 (d, J = 9.2, 2H).
EXAMPLE 481 2-[4~(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzooxazo!e, The title compound was prepared according to the procedure for EXAMPLE 11, using 4-(2-chloro-ethyl)-morphoiine. MS (ESI): mass calculated for CigHsoNaCU, 340.14; m/z found, 341.1 [M+Hf. 1H NMR (400 MHz, CDC!3); 288 544938 7.51 (d, J = 7.1, 1H), 7.42 (d, J = 7.2, 1H), 7.36-7.30 (m, 2H), 7.29-7.20 (m, 2H), 7.03-6.95 (m, 2H), 4.14 (t, J = 5.7, 2H), 3.80-3.72 (m, 4H), 2.83 (t, J = 5.7, 2H), 2.60 (t, J = 4.6, 4H).
EXAMPLE 482 2-[4-(2-Morpholin-4~yl-ethoxy)-phenoxy]-benzothiazole.
The title compound was prepared according to the procedure for EXAMPLE 10 12, using 4-(2-chloro-ethyl)-morpholine and 2-chloro-benzothiazoie. MS (ESI); mass calculated for C19H20N2O3S, 35; m/z found, 341.1 [M+H]+. 1H 6.12 NMR (400 MHz, CDCI3): 7.74 (d, J= 7.6, 1H), 7.66 (d, J = 7.3, 1H), 7.39 (W= 7.3, 1H), 7.31-7.20 (m, 3H), 7.00-6.93 (m, 2H), 4.14 (t, J = 5.7, 2H), 3.80-3.72 (m, 4H), 2.83 (t, J = 5.7, 2H), 2.60 (t, J = 4.6, 4H).
EXAMPLE 483 2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-benzothiazoie.
The title compound was prepared according to the procedure for EXAMPLE 12, using 4-(2-chloro-ethyl)-piperidine and 2-chioro-benzothiazole. MS (ESI): mass calculated for C20H22N2O2S, 354.14; m/z found, 355.1 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.74 The title compound was prepared according to the procedure for EXAMPLE 11, using (2-chloro-ethyl)-diethy!-amine. MS (ESI): mass calculated for C19H22N2O3, 326.16; m/z found, 327.1 [M+Hf. 1H NMR (400 MHz, CDC!3): 7.51 (d, J = 7.6, 1H), 7.42 (d, J = 7.2, 1H), 7.36-7.29 (m, 2H), 7.28-7.19 (m, 2H), 7.02-6.94 (m, 2H), 4.07 (t, J = 6.3, 2H), 2.90 (t, J = 6.3, 2H), 2.65 (q, J = 10 7.2, 4H), 1.09 (t, J= 7.1, 6H).
Assay Methods Assay results providd herein are illustrative results of the assays that were performed for compounds of this invention.
Recombinant Human LTA4 Hydrolase Assay for LTA4 Hydrolase Inhibitor Activity Compounds of the present invention were tested for LTA4 hydrolase inhibitor activity against recombinant human LTA4 hydrolase (rhLTA4H). Vectors were prepared and used to express rhLTA4H essentially as follows: LTA4 hydrolase encoding DNA was amplified by polymerase chain reaction (PCR) using a human placental cDNA library as a template. Oligonucleotide primers for the PCR reaction were based on the 5'-end, and the complement of the 3"-end, of the published nucleotide sequence for the coding region of the human LTA4 hydrolase gene (C.D. Funk et al., Proc. Natl. Acad. Sci. USA 1987, 84:6677-6681). The amplified 1,9 kb DNA fragment encoding LTA4 hydrolase was isolated and cloned into the pFastBad vector (Invitrogen). Recombinant baculovirus was generated as described by the manufacturer, and used to infect Spodoptera frugiperda (Sf-9) cells. Recombinant LTA4 hydrolase enzyme was purified from the infected Sf-9 cells essentially as described by J.K. Gierse et al. (Protein Expression and Purification 1993, 4:358-366). The purified enzyme solution was adjusted to contain 0.29 mg/mL 290 544938 LTA4 hydrolase, 50 mM Tris (pH 8.0), 150 mM NaCI, 5 mM dithiothreitoi, 50% glycerol, and EDTA-free Complete protease inhibitor cocktail (Roche). The specific activity of the enzyme was about 3.8 pmol/min/mg, LTA4 substrate was prepared from the methyl ester of LTA4 (Cayman 5 Chemical) by treatment with 67 equiv of NaOH under nitrogen at room temperature for 40 min. The LTA4 substrate in its free acid form was kept frozen at -80 °C until needed. Each compound was diluted to different concentrations in assay buffer (0.1 M potassium phosphate (pH 7.4), 5 mg/mL fatty acid free BSA) containing 10% DMSO, A 25-uL aliquot of each compound 10 dilution was incubated for 10 min at room temperature with an equal volume of assay buffer containing 36 ng of recombinant human LTA4H. The solution was then adjusted to 200 pL with assay buffer. LTA4 (free acid) was thawed and diluted in assay buffer to a concentration of 357 ng/m!_, and 25 pL (9 ng) of LTA4 substrate was added to the reaction mixture (total volume = 225 pL) at 15 time zero. Each reaction was carried out at room temperature for 10 min. The reaction was stopped by diluting 10 pL of the reaction mixture with 200 pL of assay buffer. LTB4 was quantified in the diluted sample by a commercially available enzyme-linked immunoassay (Cayman Chemical Co.), as recommended by the manufacturer. Positive controls, under essentially 20 identical conditions but without addition of an inhibitor compound, and negative controls, containing all assay components except enzyme, were routinely run in each experiment. IC6o values were determined by fitting the activity data at different compound concentrations to a 4-parameter equation using the Grafit program (Erithacus software).
The IC50 values presented in the tables below should be expected to fall within the typical three-fold variability of assays of this type. The values presented here are, in general, an average of one to three determinations.
Table 1 Example IC50 Example IC50 Example IC50 (nM) (nM) (nM) 11 6 45 94 1 291 544938 13 2 46 17 135 92 14 9 59 136 27 7 77 271 2 36 14 78 3 481 55 44 8 92 1 484 19 Table 2 Example IC50 (nM) Example ICgo (nM) Example IC50 (nM) 12 100 176 12 298 22 180 2 302 60 18 6 183 18 325 12 22 7 192 3 328 22 23 1 195 58 331 13 4 202 4 334 100 31 17 206 4 336 24 80 23 207 16 353 7 81 211 9 357 45 102 3 214 18 358 11 104 14 224 14 359 48 / 109 21 225 360 '33 110 40 250 26 361 8 143 64 251 16 363 4 146 43 255 1 366 39 147 33 259 14 380 6 150 1 261 33 389 2 153 8 262 4 419 4 155 9 263 437 21 156 7 265 112 446 8 157 1 270 16 447 28 161 1 274 j 29 450 7 292 544938 163 9 285 76 454 4 167 37 287 28 462 27 168 27 288 4 471 19 169 32 296 33 479 7 172 27 294 6 483 45 Table 3 Example IC50 Example IC50 (nM) (nM) 37 134 110 123 4 230 36 127 29 231 18 132 139 485 39 133 111 LTB4 Production by Calcium lonophore-Stimulated Murine Blood for LTA4H Inhibitor Activity CD-1 mice were sacrificed, and blood was coliected in heparin-containing syringes by cardiac puncture. The blood was diluted 1:15 with RPMi-1640 medium, and 200-pL aliquots of the diluted blood were add^d to 10 wells of a 96-well microtiter plate. LTA4H inhibitor test compounds were prepared at different concentrations in RPMI-1640 medium containing 1% DMSO, and 20 |mL of each test solution was added to a well containing diluted whole blood {final DMSO concentration of 0,1%). After the microtiter plate contents were incubated for 15 min at 37 °C in a humidified incubator, calcium 15 ionophore A23187 {Sigma Chemical Co., St. Louis, Mo.) was added to each sample well (final concentration = 20 ng/mL). The incubation was continued under the same conditions for an additional 10 min to allow LTB4 formation. The reaction was terminated by centrifugation (833 x g, 10 min at 4 °C), and supernatants were analyzed for LTB4 by a commercially available enzyme-20 linked immunoassay (Cayman Chemical Co.) according to the manufacturer's 544938 instructions. Positive controls, under essentially identical conditions but without addition of an inhibitor compound, and negative unstimulated controls, containing all assay components except calcium ionophore, were routinely run in each experiment, IC50 values were determined by fitting the activity data at 5 different compound concentrations to a 4-parameter equation using the Grafit program {Erithacus software).
Table 4 Example ICso (nM) Example IC50 (nM) Example IC50 (nM) 11 44 27 143 94 72 13 41 44 23 481 264 14 89 46 29 484 11 Table 5 Example IC50 (nM) Example IC50 (nM) Example ICso (nM) 251 250 99 328 143 18 162 198 39 331 85 22 123 206 43 334 453 23 93 207 81 336 153 81 41 251 159 359 446 102 55 259 49 360 246 104 520 261 81 380 17 109 189 263 49 437 105 150 52 274 331 446 131 155 127 288 57 447 240 156 2000 296 133 462 144 161 100 298 69 483 161 180 302 212 294 544938 Table 6 Example IC50 Example IC50 (nM) (nM) 127 376 133 290 132 347 134 436 Murine arachidonic acid-induced inflammation model LTA4H inhibitor compounds of the present invention were dissolved in % cyclodextran/H20 at a concentration of 3 mg/mL The solutions were administered by oral gavage to female Balb/c mice weighing approximately 20 grams each (0.2 mL per mouse, 30 mg of LTA4H inhibitor compound per kg). Sixty minutes after being administered an LTA4 inhibitor, each mouse received 10 topical application of 20 pL of arachidonic acid (100 mg/mL in acetone) to the left ear and 20 pL of acetone only to the right ear. After 3 h, the mice were sacrificed, blood was withdrawn in heparinized syringes, and 8 mm ear biopsies were taken. Ear biopsies were weighed to determine edema and then frozen at -80 °C until needed for determination of neutrophil influx. 15 One hundred-microliter aliquots of heparinized blood were added to wells of a microtiter piate, along with equal volumes of RPMi-1640 medjum, and calcium ionophore A23187 was added to each sample well (final I concentration = 20 ng/pL). The microtiter plate contents were incubated for 10 min at 37 °C in a humidified incubator. The reaction was terminated by 20 centrifugation (833 x g, 10 min at 4 °C). Supernatants were analyzed for LTB4 by a commercially available enzyme-linked immunoassay (Cayman Chemical Co.) in accordance with the manufacturer's instructions. The percent inhibition of ex vivo stimulated LTB4 production (% Inh. LTB4) was determined by comparison to animals treated identically except that the solution 25 admininstered by oral gavage was devoid of inhibitor compound.
Neutrophil influx was quantified by measuring the activity of myeloperoxidase (MPO), a neutrophil-specific enzyme. The ear biopsies were homogenized in 0.5 mL extraction buffer (0.3 M sucrose, 0.22% (w/v) 295 544938 hexadecyl trimethyl ammonium bromide (CTAB), and 2,5 mM citrate prepared from 0.5 M citrate stock solution (pH 5,0)). Debris was removed by centrifugation at 14000 x g for 10 min, Aliquots of 10 pL of the resulting supernatant were added to welis of a microtiter plate, along with 90-jjL aliquots 5 of dilution buffer (10 mM citrate, 0.22% CTAB), followed by addition of 20 jjL TMB liquid substrate system (Sigma Chemical Co.) to each sample well. The microtiter plate contents were held at room temperature for 1 h. The reaction was stopped by addition of 100 pL 1 M H2SO4 to each sample well, and the myeloperoxidase activity in each sample was determined from the absorbance 10 at 405 nm. The background value from the right ear, treated only with acetone, was subtracted from that for the left ear, treated with arachidonic acid in acetone, for each animal. The percent inhibition of neutrophil influx (% Inh. MPO) by compounds of the invention was determined by comparison to animals treated identically, except that the solution administered by oral 15 gavage was devoid of inhibitor compound.
Table 7 Example % Inh. LTB4 % Inh. MPO 11 83 95 14 81 56 27 50 72 Table 8 Example % Inh. LTB4 % Inh. MPO Example % Inh. LTB4 % Inh. MPO 32 29 251 79 66 18 78 83 259 95 74 22 79 79 263 0 19 23 67 84 274 93 87 81 78 83 325 76 67 109 51 44 336 67 0 296 544938 150 81 91 360 87 88 155 96 93 361 86 90 180 87 87 446 64 43 250 80 94 447 90 48 206 67 76 471 90 89 250 80 94 Having described the invention in specific detail and exemplified the manner in which it may be carried into practice, it will be apparent to those skilled in the art that innumerable variations, appiications, modifications, and 5 extensions of the basic principles involved may be made without departing from its spirit or scope. It is to be understood that the foregoing is merely exemplary and the present invention is not to be limited to the specific form or arrangements of parts herein described and shown. 1.
What is claimed is: / 297 Docket PRD2089PCT 544938

Claims (9)

1.WHAT WE CLAIM IS: 1. The use, in the preparation of a medicament for treating, preventing or inhibiting inflammation in a subject, of at least one LTA4H modulator selected from compounds of formula (I): R -N \3 (i) wherein 15 X is selected from the group consisting of NR5, O, and S, with R5 being one of H and CH3; Y is selected from the group consisting of CH2, and O; Z is selected from the group consisting of O and bond; W is selected from the group consisting of CH2 and CHR1-CH2, with R1 being 20 one of H and OH, wherein the Reattached carbon member in said CHR1-CH2 is not directly attached to the nitrogen member to which said W is attached; R4 is selected from the group consisting of H, OCH3, CI, F, Br, I, OH, NH2, CN, CF3 and CH3; R6 is H or F; and 25 R2 and R3 are each independently selected from the group consisting of A) H, Ci./alkyl, C3.7alkenyl, wherein the carbon in said alkenyl that is attached to the nitrogen member has only single bonds, Cs^alkynyl, wherein the carbon in said aikynyi that is attached to the nitrogen member has only single bonds, Cs^cycloalkyl optionally benzofused, 30 Cs-7cycloalkenyl, ~C3.7CycloaIkylCi-7aikyl, -C^alkylCs-TcycIoalkyi and phenyl, wherein each of the substituents A) is independently substituted with 0, 1, or 2 RQ, and each of said Ru is a substituent at Q 298 Docket PRD2089PCT a carbon member that is at least one carbon member removed from the nitrogen member; B) a substituent HetRa; C) -Ci.7aikylC(0)Rx, optionally substituted with CH2RAr or CH2RA^; D) -C2-5alkylC(0)Rx, wherein two valence allowed carbon members in the C2-5alkyl of said -C2.5alkylC(0)Rx are part of a saturated C3_ scarbocycle; E) -C2-5aikylOH wherein two valence allowed carbon members in the C2.5alkyi of said -C2-sa!kyiOH are part of a saturated C3.6carbocycle; F) ~C0-4alkylphenyl, wherein the phenyl in said -Co^alkylphenyl is fused at two adjacent carbon members in said phenyl to Rf, or is benzofused; G) -Co-4alkylAr6, where Ar6 is a 6-membered heteroaryl having a carbon member point of attachment and having one or two -N= heteroatom members, and benzofused; H) -Co-4alkylAr5, where Ar5 is a 5-membered heteroaryl, having one heteroatom member selected from the group consisting of O, S, and >NRY, and having 0 or 1 -N= additional heteroatom member, optionally containing two carbonyl groups, and optionally benzofused; I) -Ci^alkylAr5, where Ar5 is a 5-membered heteroaryl containing 3 or 4 nitrogen members, optionally substituted with RY, and having a valence allowed site as a point of attachment; J) -C0-4alkylAr6"6, where Ar6"6 is a Co-4aikyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has one or two -N= heteroatom members; K) -C0.4alkylAr6"5, where Ar6'5 is a Co^alkyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRY, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is -N=; and L) one of 2-{4-ethyl-phenoxy)-benzothiazole, 2-(4-ethyi-phenoxy)-benzooxazole, and 2-(4-ethyl-phenoxy)-1H-benzoirni$3ZQle; 299 I 3 bn 2009 Docket PRD2089PCT 544933 M) S02Ci.4alky!; alternatively R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of i) ■ a 4-7 membered heterocyclic ring HetRb, said 4-7 membered heterocyclic ring HetRb having one heteroatom member that is said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different substitution members, said substituents being selected from the group consisting of -RY, -CN, -C(0)Ry, -Co-4alkylC02RY -Co-4aikylC(0)C02RY, -C0-4alkylORY, -Co.4aikyiC(0}NRYRz, -C0-4atkyiNRYC(O)Rz, -C(0)NRz0RY, -C0^alky!NRYC(O)CH2ORY -Co-4alkylNRYC(0)CH2C(0)RYJ -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz! -C0-4afkyiNRYC(S)NRYRz, -NRYC(0)C02RY,-NRYRz, -C0.4aIkyINRwS02RY, 1, 3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazoi-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol~5~yi, RY-triazolylt 2-RY-2H-tetrazol-5-yi, pyrroiidine-2-thion-l-yl, piperidine-2-thion-1-yl, -C0-4alkylC(O)N(RY)(SO2RY), -C0-4afkylN(RY)(SO2)NRYRY, -C0- j^-CN ivj-CN N' "N"rY ^N^S-rY 4alkylN(RY}(S02)NRYC02RY haio, h h s h n-oj n-oh ^o-Ry "^n ' y h ~N' ^N^N"rY h , and R ii) a 5-7 membered heterocyclic ring HetRc, said 5-7 heterocyclic ring HetR° having one additional heteroatom member separated from said attachment nitrogen by at least one carbon members, said additional heteroatom member being selected from the group consisting of O, S(=0)o_2, and >NRM, said 5-7 membered heterocyclic ring HetRc having 0 or 1 carbonyl members, and being 300 2 3 APR Docket PRD2089PCT 544938 25 30 substituted with 0, 1, or 2 substituents at the same or at different carbon substitution members, said substituents being selected from the group consisting of -C(0)RY, -C02Ry -C3-4aikyiC02RY and Rz; iii) one of imidazoIidin-1-yl, 2-imidazolin-1-yl, pyrazoi-1-yl, imidazol-1-yt, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl, pyrroi-1-yl, 2-pyrrolin-1-yl, and 3-pyrrolin-1-y!, wherein each of said 2W-tetrazo!-2~yl and 1 H-tetrazol-1-yl is substituted at the carbon member with 0 or 1 of -Co^aikylR2, -CG.4aikyISRY, -Co-4alkylC02RY, and substituent HetRa; and iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, indol-1 -yl, isoindol-2-yi, indolin-1-yl, benzimidazol-1-yl, 2,8-diaza-spiro[4.5]decan~1-one-8-yl, 4-{[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)--amino]-methyi}-piperidin-1-yl, 4-{[(2-amino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 3,9-diaza-spiro[5.5]undecane-3-carboxyfic acid-9-yl tert-butyl ester, 4-oxo-1-phenyi-i,3,8-triaza-spiro[4.5]dec-8-yl, and 4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl; substituent HetRa is a 4-7 membered heterocyclic ring having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from said carbon member point of attachment by at least 1 additional carbon member; RK is selected from the group consisting of H, -C1_4alkyl, -C0-4alky!RAr each optionally substituted with 1, 2, or 3 substituents RN Rl is selected from the group consisting of-C02Rs and -C(0)NRsRs; RM is selected from the group consisting of Rz, indoi-7-yl, -S02RY, -C3. 4alkylC02RY, -C02RY, -C(0)NRz0Ry, -C(0)RY -C(0)CMalkyl0RY, -CQ.4alkyiC(0}NRsRs', CNRY, provided that said additional heteroatom member is separated by at least two carbon 15 members from said nitrogen member to which said Rs and Rs are attached, and provided that where RY is CcMalkylRAr, then RAr is not substituted with Rl; Rw is selected from the group consisting of Ry, and -C3_7cycioalkyl; Rx is selected from the group consisting of -ORY, -NRyRz, -Ci^alkyl, and 20 -C0-4alky!RAr; Ry is selected from the group consisting of H, -C-,.4alkyl, -C0.4alkylRAr and -Co-4alkylRAr, each optionally substituted with 1, 2, or 3 substituents RN; Rz is selected from the group consisting of RY, -C2-4alkylORY, -C1.2aikylC02RY,-C1.2alkylC(0)NRsRs , and -C2..4alkylNRsRs; 25 when RY and Rz are attached to a nitrogen member, RY and Rz are selected as defined above, or RY and Rz are taken together with the RY- and Rz-attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group consisting of O, S, and >NRM, said 4-7 membered heterocyclic ring HetRd 30 having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring 302 ■C %F'- V Z 3 APR J. Docket PRD2Q89PCT 54493s 10 15 20 25 HetRd having 0 or 1 valence allowed carbon members substituted with at least one of RM, -CO2H, and -Co-ialkylORY; RAr is a moiety with a carbon member attachment point and said moiety is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and pyrazinyf, wherein each valence allowed carbon member in each of said moieties is independently substituted with at least one of 0, 1, 2 or 3 RN, and 0 or 1 Rl; R is a 3-8 membered ring, having 0, 1 or 2 heteroatom members selected from the group consisting of O, S, N, and >NRV, having 0, 1, or 2 unsaturated bonds, having 0 or 1 carbonyl members, wherein each valence allowed member in each of said rings is independently substituted with 0, 1, or 2 RK; and Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members; or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof.
2. A use as in claim 1, wherein said R4 is H.
3. A use as in claim 1, wherein said R2 and R3 are each independently selected from the group consisting of A), B), C), D), E), and I), as defined in claim 1.
4. A use as in claim 1, wherein said R2 and R3 are each independently selected from the group A), as defined in claim 1.
5. A use as in claim 1, wherein said R2 and R3 are each independently selected from the group B), as defined in claim 1.
6. A use as in claim 1, wherein said R2 and R3 are each independently selected from the group C), as defined in claim 1. 303 Docket PRD2089PCT
7. A use as in claim 1, wherein said R2 and R3 are each independently selected from the group D), as defined in claim 1.
8. A use as in claim 1, wherein said R2 and R3 are each independently 5 selected from the group E), as defined in claim 1. selected from the group I), as defined in claim 1. 10 10. A use as in claim 1, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of i) and ii), as defined in claim 1. 15 11. A use as in claim 1, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group i), as defined in claim 1. 20 12. A use as in claim 1, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group ii), as defined in claim 1. 25 13. A use as in claim 1, wherein said inflammation is associated with at least one of asthma, chronic obstructed pulmonary disease, atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and psoriasis. 14. A use as in claim 1, wherein said at least one LTA4H modulator is one of: 2-[4-(2-Piperidin-1 -yl-ethoxy)-phenoxyj-benzooxazoie;
9. A use as in claim 1, wherein said R2 and R3 are each independently 30 304 Docket PRD2089PCT (1-{2-[4-(Benzooxazol-2-yloxy)~phenoxy]ethyl}-piperidin~4-yI)-methanol; 1-{2~{4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol; {2-[4-(BenzooxazoI-2-yioxy)-phenoxy]-ethyi}-dibuty!-amine; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yi)~ methanoi; 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-phenyl-piperidin-4-ol; 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-benzy!-piperidin-4-ol; 2-[4-(2-Piperidin~1-yi-ethyl)-phenoxy]-benzooxazoie; {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyf}-cyclohexyi-ethyi- arnine; 1 -{3-[4-{ Be nzooxazol-2-yloxy)-p heny !]-propyl}-p iperid in -4-oi; 1-{3-[4-(Benzooxazol-2-y[oxy)-phenoxy]-2-hydroxy-propyl}-4- phenyi-piperidin-4-ol; 1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]~piperidine-4-carboxylic acid etbyi ester; 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzooxazoie; {3-[4-(Benzooxazol-2-yloxy)-phenoxy)-propyI}-dimethy!-amine; {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine; and 2-[4-(2-Azepan-1 -yl-ethoxy)~phenoxy]-benzooxazoIe. 15. A use as in claim 1, wherein said at least one LTA4H modulator is one of: 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-4-phenyi-piperidin-4-oi; {2-[4~(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyi-ethyl-amine; 2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidine-4-carbonitrile; 305 Docket PRD2G89PCT 544938 1 -(1 -{2-[4-(Benzooxazol-2-yloxy)~phenoxy]-ethyl}~4-phenyl-piperidin-4-yl)-ethanone; 2-{4-[2-(4-MethyI~piperidin-1-yl)-ethoxyj-phenoxy}-benzooxazole; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-4-(4-chloro-phenyl)- piperidin-4-ol; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-4~(4-bromo-phenyl)-piperidin-4-ol; 1-{2-[4-(Benzooxazoi-2-yloxy)-phenoxy]~ethyi}~4-(4-chloro-3-trifluoromethy!-phenyl)-piperidin-4-oi; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy)-ethy!}-4-benzyl-piperidin-4-oi; {2-[4-(Benzooxazo!~2-yloxy)-phenoxy]-ethyi}-cyclohexyi-methyl-amine; and {2-[4-(Benzooxazoi-2-yloxy)-phenoxy]-ethyl}-cyciopropyimethyi-propyl-amine. 16. A use as in claim 1, wherein said at least one LTA4H modulator is one of: {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-butyl-ethyl-amine; 2-{{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-benzyl-amino)-ethanoi; 2-{4-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3-yi)- methanol; 2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyI}-propyl-amino)-ethanol; 2-[4-(2-Azetidin-1-yl-ethoxy)-phenoxy]-benzooxazo!e; /V-(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yi)-2- phenyl-acetamide; 1~{2-[4~(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidine-3-carboxytic acid ethyl ester; 2-{4-[3-(4-Phenyi-piperidin-1-yl)-propoxy]-phenoxy}-benzooxazo!e; 306 Docket PRD2089PGT 544938 1-{2-[4-(Benzooxazol-2~yloxy)-phenyi]-ethy!}-4~phenyl-piperidiiv4~ ol; {2-[4-(Benzooxazoi-2-yloxy)-phenylj-ethyl}-cyclohexyl-ethy!-amine; 2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzooxazole; and 2-[4-(2-Azepan~1-yl-ethyl)-phenoxy]-benzooxazole. 17. A use as in claim 1, wherein said at least one LTA4H modulator is one of: {2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyf}-cyclopropylmethyl-propyl-amine; {2-[4-(Benzooxazol-2-yloxy)~phenyi]-ethyl}-dibutyl-amine; 1-{2-[4-(Benzooxazol-2-yloxy)-pheny!]-ethy!}-piperidin-4-o!; 1-{2-[4-(Benzooxazol-2-yloxy)-phenyI]-ethyl}-piperidine-4-carboxylic acid methyl ester; 1-{3-[4-(BenzooxazoI-2-yloxy)-phenyi]»propyl}-4-phenyf-piperidin-4-ol; 2-[4-(3-Piperidin-1-yl-propyl)-phenoxy]-benzooxazo!e; {3-[4-(Benzooxazol-2-yloxy)~phenyi]-propyl}-dibutyi-amine; {3-[4-(Benzooxazol-2-yloxy)-phenyl3-propyl}-cyc!opropylmethyi-propyl-amine; 1-[4-(Benzooxazol-2-yloxy)-phenoxy]-3-pyrrolidin-1-yl-propan-2-ol; 1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-4-phenyl- piperidin-4-ol; 1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylic acid amide 2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzooxazole; and {2-[4~(Benzooxazol-2-yioxy)-phenoxy]-ethyl}-diethyl-amine, 18. A use as in claim 1, wherein said at least one LTA4H modulator is one of: {2-[4-{6-Chloro-benzothiazol-2-yioxy)-phenoxy]-ethy!}-diethyi- amine; 1-{2-[4-(Benzothiazo!-2-yioxy)-phenoxy]-ethyl}-pipendin-4-ol; 5 307 NRY, and having 0 or 1 -N= additional heteroatom member, optionally containing two carbonyl groups, and optionally benzofused; I) -Ci_4alkylAr5, where Ar5 is a 5-membered heteroaryl containing 3 or 4 nitrogen members, optionally substituted with RY, and having a valence allowed site as a point of attachment; J) -Co-4alkylAr6"6, where Ar6"6 is a Co^alkyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has one or two -N= heteroatom members; K) -Co^alkylAr6"5, where Ar6"5 is a Co.4aIkyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRY, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is -N^; and L) one of 2-(4-ethyS-phenoxy)-benzothiazole, 2-(4-ethyl-phenoxy)-benzooxazole, and 2-(4-ethyi-phenoxy)-1 H-benzoimidazole; M) S02Ci^alkyl; alternatively R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of 331 Docket PRD2089PCT 544933 i) a 4-7 membered heterocyclic ring HetRb, said 4-7 membered heterocyclic ring HetRb having one heteroatom member that is said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different substitution members, said substituents being selected from the group consisting of -RY, -CN, -C(0)Ry, -Co.4alkylC02RY, -C0-4alky!C(O)CO2RY -C0. 4alkylORY, -C0^alkylC(O)NRYRz, -Co-4aikylNRYC(0)Rz, -C(0)NRz0RY, -C0^alkylNRYC(O)CH2ORY, -C0-4alkylNRYC(O)CH2C(O)RY, -C0-4alkylNRYCO2RY, -C0.4alkylNRYC(O)NRYRz, -C0-4alkylNRYC(S)NRYRz -NRyC(0)C02Ry,-NRyRz, -C0^alkylNRwSO2RY 1,3-dihydro-indoi-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, l-RY-1H-tetrazol-5-yi, RY-triazolyl, 2-RY-2W-tetrazol-5-yl, pyrrolidine-2-thion-1-yl, piperidine-2-thion-l-yl, -Co-4alkylC(0)N(RY)(S02RY), -C0.4alkyiN{RY)(SO2)NRYRY, -Coil) a 5-7 membered heterocyclic ring HetRc, said 5-7 heterocyclic ring HetRc having one additional heteroatom member separated from said attachment nitrogen by at least one carbon members, said additional heteroatom member being selected from the group consisting of O, S(=0)o_2, and >NRM, said 5-7 membered heterocyclic ring HetRc having 0 or 1 carbonyl members, and being substituted with 0, 1, or 2 substituents at the same or at different carbon substitution members, said substituents being selected from the group consisting of -C(0)RY, -C02Ry -C3-4alkylC02RY and R2; iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazol-1-yi, imidazol-1 -yl, 2H-tetrazol-2~yl, 1 H-tetrazol-1-yl, pyrrol-1-yl, 2-pyrrolin-1- 4aIkyIN(Ry)(S 02)NRyC02Ry, halo, H H H 332 2 3 APR 2009 ] Docket PRD2089PCT 544938 yl, and 3-pyrrolin-1-yl, wherein each of said 2H-tetrazol~2-yl and 1H-tetrazol-1-yl is substituted at the carbon member with 0 or 1 of -CcMalkyiR2, ^C0-4alkylSRYI -C0-4alkyiCO2RY and substituent HetRa; and 5 iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl, 1,2,3,4-tetrahydro- isoquinolin-2-yl, indol-1-yl, isoindoi-2-yl, indolin-1 -yl, benzimidazol-1-y!, 2,8-diaza-spiro[4.53decan-1-one-8-yl, 4-{[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 4-{[{2-amino-cyclobutanecarbonyl)-10 amino]-methyl}-piperidin-1 -yi, 3,9-diaza~spiro(5.51undecane-3- carboxylic acid-9-yl tert-butyl ester, 4-oxo-1-phenyl-1,3,8-triaza-spiro[4,5]dec-8-yl, and 4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl; wherein 15 substituent HetRa is a 4-7 membered heterocyclic ring having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from said carbon member point of attachment by at least 1 additional carbon member; 20 Rk is selected from the group consisting of H, -C^alkyl, -Co-4alkylRAr each optionally substituted with 1, 2, or 3 substituents RN RL is selected from the group consisting of -C02RS and -C(0)NRsRs; Rm is selected from the group consisting of Rz, indol-7-yi, -S02RY, -C3. 4alkyiC02RY, -C02RY, -C(0)NRz0RY, -C(0)RY, -C(0)CMalkyl0RY, -25 Co-4aikylC(0)NRsRs, C0.4alkylC(O)CO2RY, 1,3-dihydro-indol-2-one-1 -yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-y!, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol-5-yl and -C0.4aikylC(O)N(RY)(SO2RY), each optionally substituted with 1, 2 or 3 substituents RN; RN is selected from the group consisting of OCH3, CI, F, Br, I, OH, NH2, CN, 30 CF3, CH3) 0C(0)CH3i and N02; 333 Docket PRD2089PCT 544933 Rq is selected from the group consisting of fluoro, chloro, bromo, iodo, trifiuorornethyi, trichloromethy!, -CN, -Ci^aikyl, -Co-4alkyiRAr, ~Co-4alkylRAr, -C0-4atkylORY, -Cr>4alkylC02RY, -C0-4aikylNRYRz, -C0-4aikyiNRYCORY1 -C0-4alkylNRYCONRYRz, -C0-4aIkylNRYSO2RY! and -C0-4a!ky[SRY; 5 Rs and Rs are independently selected from the group consisting of H, -Chalky!, and -Co-4alkylphenyl; alternatively, Rs and Rs are taken together with the nitrogen member to which said Rs and Rs are attached to form a 4-7 membered heterocyclic ring having 0 or 1 additional heteroatom member selected from the group consisting of O, S, and >NRY, provided that said 10 additional heteroatom member is separated by at least two carbon members from said nitrogen member to which said Rs and Rs are attached, and provided that where RY is Co-4aikylRAr, then RAr is not substituted with RL; Rw is selected from the group consisting of RY, and -C3_7cyc(oalkyl; 15 Rx is selected from the group consisting of -ORY, -NRyR2, -C^alkyl, and -C0-4aikylRAr; Ry is selected from the group consisting of H, -Ci^alkyl, -Co^alkylRAr and -C0^aiky!RAr, each optionally substituted with 1, 2, or 3 substituents RN; Rz is selected from the group consisting of RY, -C2-4alkylORY, 20 -C1.2aikyiC02RY -Ci„2alkylC(0)NRsRs>, and -C2-4alkyINRsRs'; when Ry and Rzare attached to a nitrogen member, RYand Rzare selected as defined above, or RY and Rz are taken together with the RY- and Rz-attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group 25 consisting of O, S, and >NRM, said 4-7 membered heterocyclic ring HetRd having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring HetRd having 0 or 1 valence allowed carbon members substituted with at least one of RM, -C02H, and -Co-ialky!ORY; RAris a moiety with a carbon member attachment point and said moiety is 30 selected from the group consisting of phenyl, pyridyl, pyrtmidyl, and pyrazinyi, wherein each valence allowed carbon member in each of said moieties is independently substituted with at least one of 0, 1, 2 or 3 RN, and 0 or 1 RL; 334 Docket PRD2089PCT RAr is a 3-8 membered ring, having 0, 1 or 2 heteroatom members selected from the group consisting of O, S, N, and >NRY, having 0, 1, or 2 unsaturated bonds, having 0 or 1 carbonyl members, wherein each valence allowed member in each of said rings is independently substituted with 0, 1, or 2 Rk; and Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members; or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof. 47. A pharmaceuticai composition as in claim 46, wherein said at least one compound of formula (I) is at least one compound of formula (If): or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof, wherein R4, R6, X, Y, Z, and W are defined as in compound of formula (I), R2 is defined as R2 in compound of formula (I), and R3 is defined as R3 in compound of formula (I), provided that (a) at least one of said R2 and R3 is not ethyl when one selection in the group consisting of selections (s1), (s2), (s3), and (s4), is satisfied, and each of said selections is specified as (s1): R4 is H, Z is O, W is CH2, Y is CH2, and X is S; (s2): R4 is H, Z is O, W is CH2, Y is CH2, and X is NH; z w—N; 335 Docket PRD2089PCT (s3): R4 is H, Z is 0, W is CH2j Y is O, and X is S; (s4): R4 is 5-chloro, Z is O, W is CH2, Y is CH2, and X is S; (b) further provided that when Z is bond, Y is CH2, W is CHR1-CH2, r1 's H, and one of R2 and R3 is 1H-imidazoi-2-yl, then the other of R2 and R3 is selected from A1), B)-L), wherein B)-L) are as defined above for compound of formula (I), and A1) consists of H, C3-7alkenyl, wherein the carbon in said C3. 7a(kenyl that is attached to the nitrogen member has only single bonds, C3. 7aikynyi, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, C3.7cycloaikyl optionally benzofused, C5. 7cycioalkenyl, ~C3-7cycloa!kylC1.7alkyi! -Ci„7alkylC3.7cycloa!kyl; and (c) further provided that when X is S, Y is O, Z is bond, and W is CH2, then one of R2 and R3 Is not XCG when the other is Chalky!, wherein XCG is the group wherein HC16 is one of H, C-i-ealkyl, haloCi^alkyi, allyl, and C-|.6alkoxymethyl, and GO is a group attached by a carbon member that has a =0 substituent forming an amtdo group with the nitrogen member to which said GO group is attached. 48. A pharmaceutical composition as in claim 46, wherein said R4 is H. 49. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are each independently selected from the group consisting of A), B), C), D), E), and I), as defined in claim 46. 50. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are each independently selected from the group A), as defined in claim 46. CN N GO (XCG) HC16 336 Docket PRD2089PCT 544938 10 15 20 25 51. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are each independently selected from the group B), as defined in claim 46. 52. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are each independently selected from the group C), as defined in claim 46. 53. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are each independently selected from the group D), as defined in claim 46. 54. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are each independently selected from the group E), as defined in claim 46. 55. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are each independently selected from the group I), as defined in claim 46. 56. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of i) and ii), as defined in claim 46. 57. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group i), as defined in claim 46. 58. A pharmaceutical composition as in claim 46, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group ii), as defined in claim 46. 337 V Docket PRD2089PCT 544938 59, A pharmaceutical composition as in claim 46, wherein said at least one compound of formula (II) is one of: 2-[4-{2-Piperidin-1-yl-ethoxy)-phenoxy]-benzooxazole; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]ethyl}-piperidin-4-yl)- methanol; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin~4-ol; {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yl)-methanol; 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-pheny!-piperidin-4-ol; 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-benzyl-piperidin-4-ol; 2~[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-benzooxazole; {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cyclohexyi»ethyi- amine; 1-{3~[4-(Benzooxazol-2-yloxy)-phenyl3-propyl}-piperidin-4-oi; 1-{3-[4-(Benzooxazo!-2-yloxy)-phenoxy]-2-hydroxy-propy!}-4- phenyl-piperidin-4-ol; 1-[2-(4-Benzooxazol-2-y!methyl-phenoxy)-ethyl]-piperidine-4-carboxylic acid ethyl ester; 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]--benzooxazo!e; {3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyi}-dimethyl-amine; {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dimethyi-amine; and 2-[4-(2~Azepan-1-yl-ethoxy)-phenoxy]-benzooxazole. 60. A pharmaceutical composition as in claim 46, wherein said at least one compound of formula (II) is one of: 1-{2-[4-(Benzooxazol-2~yloxy)-phenoxy]-ethyl}~4-phenyl~piperidin-4-ol; {2-[4~(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine; % 338 1 3 m 2SS9 Docket PRD2089PCT 544938 2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazoIe; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}~4-phenyl-piperidine-4-carbonitriie; 1 -(1 -{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl~ piperidirt-4-yl)-ethanone; 2-{4-£2-(4-Methyl-piperidin-1-yi)-ethoxy]-phenoxy}-benzooxazole; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-piperidin-4-ol; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol; 1-{2-[4-(Benzooxazol-2-y[oxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-oi; {2"[4-(Benzooxazoi-2-yloxy).-phenoxy3-ethyl}-cyclohexyl-methy!-amine; and {2-[4-(Benzooxazoi-2-yloxy)-phenoxy]-ethyl}-cyclopropy[rnethyl-propyl-amine. 61. A pharmaceutical composition as in claim 46, wherein said at least one compound of formula (II) is one of: {2-[4-(Benzooxazol-2-y!oxy)-phenoxy]-ethyl}-butyl-ethyl-amine; 2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-benzy!-amino)~ ethanol; 2-{4-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazoie; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3-yi)- methanol; 2-({2-[4~{Benzooxazol-2-yloxy)-phenoxy]-ethyl}-propyl-amino)-ethanol; 2-[4-(2-Azetidin-1-yl-ethoxy)-phenoxy]-benzooxazole; A/-(1-{2-[4-(Benzooxazol-2-y!oxy)-phenoxy]-ethyl}-piperidin-4-yl)-2- phenyl-acetamide; 339 Docket PRD2089PCT 544938 1-{2-J4-(Benzooxazo!-2-yloxy)-phenoxy]-ethyi}-piperidine-3-carboxyiic acid ethyl ester; 2-{4-[3-(4-Phenyi-piperidin-1-yl)-propoxy]-phenoxy}-benzooxazole; 1-{2-[4-(BenzooxazoI-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ol; {2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine; 2-[4-(2-Pyrrolidin-1 -yl-ethyl)~phenoxy]-benzooxazo!e; and 2-[4-(2-Azepan-1-yl-ethy!)-phenoxy]-benzooxazole. 62. A pharmaceutical composition as in claim 46, wherein said at least one compound of formula (II) is one of: {2-[4-(Benzooxazol-2-yloxy)-phenyi]-ethyl}-cyclopropylmethyl-propyl-amine; {2-[4~(Benzooxazol~2-yloxy)-phenyl]-ethyl}-dibutyl-amine; 1-{2-[4-(Benzooxazol-2-yioxy)-pheny!]-ethyl}-piperidin-4-ol; 1-{2-[4-(Benzooxazol-2-y]oxy)-phenyi]-ethyl}-piperidine-4-carboxylic acid methyl ester; 1-{3-[4-(Benzooxazol-2-yloxy)-phenyi]-propyl}-4-phenyl-piperidin-4-of; 2-[4-(3-Piperidin-1~yl~propy!)-phenoxy]-benzooxazole; {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-dtbutyl-amine; {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cycIopropylmethyl-propyl-amine; 1~[4-(Benzooxazol~2-yloxy)-phenoxy]-3~pyrrolidin-1-yl-propan-2-ol; 1-[2-(4-Benzooxazoi-2-ylmethyl-phenoxy)-ethyl]-4-phenyl- piperidin-4-ol; 1-[2-(4-Benzooxazo!-2-ylmethyl-phenoxy)-ethyI]-ptperidine-4-carboxylic acid amide 2-[4-(2-Morpholin-4-yi-ethoxy)-phenoxy]-benzooxazole; and {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-diethyi-amine. 340 APR 2809 Docket PRD2089PCT 63. A pharmacetutica! composition as in claim 46, wherein said at least one compound of formula (II) is one of: {2-[4-(6-Ohloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-diethyl-arnine; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyf}-piperidin-4-ol; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid ethyl ester; 1-{2-[4-(Benzothiazol~2-yloxy)-phenoxy]~ethyl}-piperidine-4-carboxylic acid; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrrolidin-1-yl-methanone; 3-[(1-{2-[4-(Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-propionic acid ethyl ester; 1-{2-[4~(Benzothiazol-2-yloxy)-phenoxy3~ethyi}~piperidine-4-carboxylic acid amide; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)- pyrrolidin-2-one; 1'-{2-[4-(Benzothiazof-2-yloxy)-phenoxy]-ethyjH1,4!]bipiperidinyl- 2-one; 8-{2-[4-( Benzoth iazo l-2-yioxy)-p henoxy]-ethyl}-2,8-d iaza-spiro[4.5]decan-1-one; 2-[4-(3-Pyrrolidin-1-yl-propoxy)-phenoxy]-benzothiazole; {2-[4-(Benzothiazoi-2-yioxy)-phenyI]-ethyl}-cyclohexy!-ethyl- amine; 1-{2-[4-(Benzothiazol~2-yloxy)-phenyl]-ethyl}-piperidine-3~ carboxylic acid amide; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one; 1-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-piperidine-4-carboxylic acid methyl ester; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-y!)-(4-methyl-piperazin-1-yl)-methanone; 13 APR *009 Docket PRD2089PCT 544938 1-[2-{4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxyiic acid methyl ester; 3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyI~ amino}~propionic acid; {2-[4-{Benzothiazol-2-yloxy)-phenoxyj-ethy!}-dimethyl-amine; 2-[4-(2-Pyrrofidin-1-yl-ethoxy)-phenoxy]-benzothiazoie; {3-[4-{Benzothiazol-2-yloxy)-phertoxy]-propyl}-dimethy!-amine; 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzothiazoie; 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-benzothiazo(e; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-phenyi-piperidin- 4-oi; {2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyc!ohexyl-ethyi-amine; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy[}-4-(4-ch!oro-phenyi)-piperidin-4-ol; {2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-dibutyi-amine; 1-{2-|[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyi)-piperidin-4-ol; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chIoro-3-trifluoromethyl-phenyl)-piperidin-4-ol; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol; 1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethylH1,4']bipiperidine; (1-{2-[4-(Benzothiazol-2*-yloxy)-phenoxy]-ethyl}-piperidin-4-yi)- methanol; A/-(1-{2-[4-(Benzothiazo!-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)- 2-phenyl-acetamide; 2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazole; 2-(4-{2-[4-(2-Morpholin-4-yl-ethyI)-piperaziri-1-yl]-ethyl}-phenoxy)-benzothiazole; 1-{3-[4-(Benzothiazol-2-yloxy)-phenoxy]-propy!}-4-pheny!-piperidin-4-ol; 342 9* 'M 11 M" Docket PRD2089PCT 544938 1-{2-[4-{Benzothiazol-2-yioxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ot; 2-[4-(2-Pyrrolidin-1-yI-ethyl)-phenoxy]-benzothiazole; 2-[4-(2-Azepan-1-yi~ethyI)-phenoxy]~benzothiazole; {2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyclopropylmethyi-propyf-amine; {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyf}-dibutyl-amine; 2-[4-(2-Piperidin-1-yl~ethyl)-phenoxy]-benzothiazole; 1-{2-f4-(Benzothiazoi-2-yloxy)-pheny!]-ethyl}-piperidin-4-o(; 1-{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-piperidine~4-carboxylic acid amide; 1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyi}-piperidine-3-carboxyiic acid ethyl ester; 1-{2-[4-(Benzothiazol-2-yloxy)-phenyij-ethyl}-4-pheny!-piperidine-4-carboxylsc acid ethyl ester; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-acetic acid ethyl ester; 1-{1-{2-[4-(Benzothiazol-2-yloxy)-phenylJ-ethyl}-piperidin-4~yl)-1,3-dihydro-indol-2-one; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-pheny[]-ethyi}-piperidin-4-yl)-pyrrolidin-2-one; A/-(1-{2-f4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-2-pheriyl-acetamide; 8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,8-diaza-spiro[4.5]decan-1 -one; 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-ol; 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid ethyl ester; 1'-{2-[4-(Benzothiazol-2-yloxy)-phenylj-ethylH1,4'3bipiperidine; 2-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenoxy}-benzothiazoie; 2-(4-{2-[4-(1 -Benzyl-1 H-tetrazol-5-yl)-piperidin-1 -yI]-ethoxy}~ phenoxy)-benzothiazole; 343 Docket PRD2089PCT 544938 4-(1-{2-[4-{Benzothiazol-2-y)oxy)-phenyl]-ethyl}~p(perid!ne-4~ carbonyl)-piperazine-1-carboxylic acid ferf-butyl ester; 1-[2-(4-Benzothiazol-2-yimethyi-phenoxy)-ethyl]-piperidine-4-carboxylic acid amide; 1-{1-[2-(4-Benzothiazof-2-ylmethyj-phenoxy)-ethyl]-piperidin-4-yl}-pyrrolidin-2-one; 1-[4-{1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidine-4-carbony!)-piperazin-1-y!]-ethanone; 1-{2~[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-piperidine-4-carboxylic acid; 1-(1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yI)-pyrrolidine-2-thione; 2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-ylJ-ethanol; 2-{4-{2-[4-(Berizothiazol-2-yloxy)-phenoxy}-ethyI}-piperazin-1-yl)- 1-pyrroiidin-1-yl-ethanone; 2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-1 -morpholin-4-yl-ethanone; 1-{2-[4~(Benzothiazof-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylic acid; 1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidine-2-carboxytic acid; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-3-yi)-acetic acid; (1-{2-[4-(Berszothiazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-yl)-acetic acid ethyl ester; (1-{2-[4-(Benzothiazo]-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-carbamic acid tert-butyl ester; (1-{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyl}-piperidin-4-yl)-acetic acid; {1-{2-[4-(Benzothiazol-2-yloxy)~phenyl]-ethyl}-piperidin-3~yl)-methanol; 344 Docket PRD20.89PCT 544938 ({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-amino)-acetic acid methyl ester; (4-{2-[4-(Benzothiazol~2-yloxy)~phenoxy]-ethyl}-piperazin-1-yi)-aceticacid; 1-(1-{2-[4-(Benzothiazol-2-yfoxy)-phenoxy]-ethyl}-piperidin-4-yi)-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-y!)-5-oxo-pyrrolidine-2~carboxylic acid; 4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yi)-phenol; /V~(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-4-chloro-A/-cyclopropyl-benzene sulfonamide; 3-({2-[4-{8enzothiazol-2-yloxy)-phenoxy3-ethyi}-cyclopropylmethyl-amino)-propionic acid; 3-({2-[4-(Benzothiazoi-2~yloxy)-phenoxy]-ethyl}~isopropy!-amino)-propionic acid; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ylamine; 3-[{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-(1-methyl-piperidin-4-yl)-amino]-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-benzyi-amino)-propionic acid; 3-((1-Acetyl-piperidin-4-yi)-{2~[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-amino)-propionic acid; 4-{1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-lH-tetrazol-5-yi)-piperidine-1-carboxylic acid tert-butyl ester; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propionic acid; 3-((1-Acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yioxy)-pheny!J-ethyl}-amino)-propionic acid; 3-[{2-[4-(Benzothiazol-2-yloxy)~phenyt]-ethyl}-(1-methyi-piperidin- 4-yl)-arnino]-propionic acid; 345 Docket PRD2089PCT 544938 3-({2-[4-{Benzothiazol~2~yloxy)-phenyl]-ethy!}-cyc!opropylmethyi-amino)-proptonic acid; 3~({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropy!-amino)-propionic acid; 2-(4-{2-[4-(Benzothiazol-2-y!oxy)-phenyl]-ethyl}-piperazin-1-yl)-1-pyrroiidin-1 -yl-ethanone; {R)-1-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-piperidine-3-carboxyiic acid; 1-(1-{2-[4-(Benzothiazol~2-yloxy)-phenyl]-ethyl}-piperidin-4-y[)-1,3 dihydro-benzoimidazol-2-one; 2-(4-{2-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-ethyl}-phenoxy)~ benzothiazoie; 2-{4-[2-(4~Ethanesulfonyl~piperazin-1-yl)-ethyl]-phenoxy}-benzothiazole; 2-(4-{2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-piperazin-1-yi)-1-morphoiiri-4-yl-ethanone; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]~ethyl}-methyl-amino)-propionic acid; 3-({2-[4~(Benzothiazoi-2-yloxy)-phenyi]-ethyi}-cyciopentyl-arnino)-propionic acid; 3-({2-[4-(Benzothiazol-2-y!oxy)-phenyl]-ethyl}-cyciobutyI-amino)~ propionic acid; 3-({2-[4-(Benzothiazoi-2-yloxy)-phenyt]-ethyl}-benzyi-amino)-propionic acid; (1-{2-[4-(Benzothiazol-2-yloxy)~phenoxy]-ethyl}-piperidin-4-yl)-(4- hydroxymethyl-piperidin-1-yl)~methanone; {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amine; (1-{2"[4-(Benzothiazol-2-y!oxy)-phenoxy]-ethyl}-piperidin-4-yi)-[4- (2-hydroxy-ethyl)-piperazin-1-yl]-methanone; (1-{2-[4-{BenzQthiazol-2-yioxy)-phenoxy]-ethyl}-piperidin-4-yi)-[4- (2-hydroxy-ethyl)-piperidin-1-yl]-methanone; 2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyf-amino)- ethanoi; Docket PRD2089PCT 54493s 3-({2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propan-1-ol; 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl3-ethyl}-cyc!opropyl-amino)-butyric acid; 3-[{1-{2~[4-(Benzothiazol-2-yloxy)~phenoxy]-ethyi}-piperidine-4-carbonyi)-amino]-propionic acid; 4-({2-[4-{Benzothiazol-2-yloxy)-phenylj-ethyl}-cyciopropyl-amino)-butyronitriie; 3-{1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-propionic acid; [(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl-amino]-acetic acid; 3-{4-{2-[4-(Benzothiazo!-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yi)~ phenol; 2-(4-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazole; 2-{4-[2-(5-Piperidin-4-yl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazole; (S)-1-{1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one; {2-[4-(Benzothiazol-2-yioxy)-phenyi]-ethyl}-cyclopropyimethyi-amine; 2-[<{2-[4-( Benzoth iazol-2-yloxy )-p henyl]-ethy l}-cyc!op ropy)-a m i n o) methylj-cyclopropanecarboxylic acid ethyl ester; 4-(4-{2-[4-(BenzothiazoI-2-yioxy)~phenoxy]-ethyl}-piperazine-1-carbonyl)-benzoic acid ethyl ester; 2-[({2-[4-(Benzothiazol-2-yioxy)-phenyl3~ethy]}-cyclopropyl-amino) methyl]-cyc!opropanecarboxyiic acid; 1~({2-[4-{Benzothiazoi-2-yioxy)~phenyI]-ethyi}-cyclopropyl-amino)-propan-2-o!; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cycIopropyl-amino)-1,1,1 -trifluoro-propan-2-ol; 347 /0f fw I 3 Docket PRD2089PCT 544938 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyf-amino)-propionarnide; 3-({2-[4-(Benzothiazol-2-yloxy)-pheriyi]-ethyl}-cyclopropy!-amino)-propane-1,2-diol; 2-{4-[2-(5-Phenyi-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazole; 2-{4-[2-(5-Phenyl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazo[e; /V-{2-[4-{Benzothiazoi-2-yioxy)-phenyi]-ethyl}-/V-cyciopropyi-2-{2H-tetrazol-5-yl)-acetamide; (S)-3-({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyc!opropyl-amino)-2-methyl-propan-1-ol; (R)-3-({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropy!-amino)-2-methyl-propan-1 -ol; 2-{4-[2-(5-Methylsulfanyl-tetrazol-2-yl)-ethoxy]-phenoxy}~ benzothiazole; 2-{4-[2-(5~iVSethy[sulfariy!-tetrazoI-1-yl)~ethoxy3-phenoxy}-benzothiazole; 2-[4-(2-Tetrazol-2-yl-ethoxy)-phenoxy]-benzothiazole; 2-[4-(2~Tetrazol-1-yl-ethoxy)-phenoxy3-benzothiazole; (1/?,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxylic acid; (1S,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxylic acid; (1 /^/^-^-^-^-{Benzothiazol^-yioxyJ-phenyO-ethylamino}-cyclohexanol; (1S,2R)-2-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyfamino}-cyciohexanol; 4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-butyric acid; {.R) 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}~piperidin-4-yl)-4-hydroxy-pyrro[idin-2-one; 2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yl]~ethyi}-phenoxy)-bertzothiazole; 348 Docket PRD2089PCT 544938 (1-{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyl}-piperidin-2-yl)-methanol; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazoI~5-yl)-acetic acid ethyl ester; (1-{2-[4-(Benzothiazol-2-yloxy)~phenoxy]-ethyl}-1H-tetrazol-5-yl)-acetic acid ethyl ester; 2-{4~[2-(5-Piperidin-4-yl-tetrazol-2-yi)-ethoxy]-phenoxy}-benzothiazole hydrochloride; 7-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-spiro-[3-phthalidej-piperidine; 1-{3-[4-(Benzothiazol-2-yloxy)-phenyl]-propy!}-piperidine-4-carboxylic acid ethyl ester; 2-[4-(Benzothiazoi-2-ytoxy)-phenyl]-ethylamine hydrochloride; 2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yl]~ethoxy}-phenoxy)-benzothiazole; cis-4-{2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethylamino}-cyclohexariecarboxylic acid trifluoromethanesulfonate salt; (4-{2-[4-{Benzothiazol-2-yloxy)-phenylj-ethyl}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone; Propane-2-sulfonic acid (1-{2-[4-(benzothiazof-2-yloxy)-phenoxy] ethyl}-piperidine-4-carbonyl)-amide; (4-{2-[4-(Benzothiazol-2-yloxy)-phenyf]-ethyl}-piperazin-1-yl)-oxo-acetic acid methyl ester; N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-benzenesulfonamide trifluoromethanesulfonate salt; N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-methanesulfonamide trifluoromethanesulfonate salt; (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-oxo-acetic acid trifluoromethanesulfonate salt; (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-morpholin-4-yl-methanone; 1-(4-{2-[4-(Benzothiazol-2-yloxy)~phenyl]-ethyl}-piperazin-1-yl)-2-thiophen-2-yl-ethanone; 349 Docket PRD2089PCT 544938 (4-{2-[4-{Benzothiazol-2-ylaxy)-phenyl]-ethyl}-piperazin-1-yi)-pyridin-3-yl-methanone; (4-{2-[4-(Benzothiazol-2~yloxy)-phenyi]-ethyl}-piperazin-1-yl)-cyclopropyl-methanone; 1-(4-{2-[4-(Benzothiazol-2-y1oxy)-phenyl]-ethyl}-piperazin-1-yi)-2-methoxy-ethanone; 1-(4-{2-[4-{Benzothiazol-2~yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2,2,2-trifluoro-etharione; 4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperazine-1-carbony!)-benzoic acid; (4-{2»[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-pyridin-4-yl-methanone; (4-{2~[4-(BenzothiazoI-2~yloxy)-phenylj|-ethyl}-piperazin-1-yf)-(5-methy!-pyrazin-2-yt)-methanone; (R)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-y[)-(tetrahydro-furan-2-yl)-methanone; (S)-(4-{2-[4~(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-l-yl)-(tetrahydro-furan-2-yi)-methanone; (4-{2-[4-(Benzothiazol-2-y!oxy)-phenyl3-ethyl}-piperazin-1-yl)-(tetrahydro-furan-3-yl)-methanone; 1-(4-{2-[4-(Benzothiazol-2-yloxy)-pheriyl]-ethyt}-piperazin-1-yl)-2~ hydroxy-ethanone; 2-[2-(4-{2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-piperazin-1-yi)- 2-oxo-ethyi]-cyclopentanone; 3-(4-{2-[4-(Berizothiazoi-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-propionic acid trifluoromethanesufonate salt; 3-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyO-ethyl}-piperidin-4-yl)-oxazolidin-2-one; 4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidin-4-yI)-morpholin-3-one; 4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yi)-morphoiin-3-one; Docket PRD2089PCT 544938 3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-oxazolidirt-2-one; 1-{2-[4-(Benzothiazol~2-yloxy)-phenyI]-ethy!}-piperidine-4-carboxylic acid benzyloxy-amide; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-acetic acid; (R)-1-(1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin~4-yl)- 4-hydroxy~pyrrolidin-2-one; 1~{2-[4-{Benzothiazol-2-yloxy)-phenyl]~ethyl}-piperidine~4-carboxylic acid hydroxyamide; (S)-1-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyf]-ethyi}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-carbamic acid tert-butyl ester; 2-{4-[2-(4-Fiuoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazoie; 2-{4-[2-(4,4-Dif!uoro-piperidin-1-yi)-ethy[]-phenoxy}~benzothiazole; (R)-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-pyrrolidin-3-ol; N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-formamide; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-piperidin-4-yl)-urea; 1 -(1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethy!}-piperidin-4-yl)-3-cyano-2-phenyl-isourea; 1-(1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-methyi-isothiourea; N-(1-{2-[4-(Berizothiazol-2-y!oxy)-phenyl]-ethyl}-piperidin-4-y!)-methanesulfonamide; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-p!peridin-4-yl)-3-cyano-2-methyl-guanidirte; 8-{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one; 8-{2-[4-(Benzothiazo!-2-y(oxy)-pheny!]-ethyl}~1,3,8-triaza-spiro^.SJdecane^^-dione; Docket PRD2089PCT 544938 (1-{2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-carbamic acid tert-butyl ester; N-(1-{2-[4-(Benzothiazol~2-yloxy)-phenyl]-ethyl}-piperidin-4-yi)-N-methyi-acetamide; N-(1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-methyl-methanesulfonamide; Acetic acid [(1-{2-[4-{benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-methyl-carbamoyl]-methyl ester; N-(1-{2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyl}-piperidin-4-yi)-N-acetamide; Acetic acid (1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ylcarbamoyl)-methyi ester; 2-({2-[4-(Benzothiazol-2-yloxy)-pheny}]-ethyl}-methyi-amino)-3-(1 H-fmidazol-2-yl)-propionic acid; 2-(4-{2-[4-{3-Nitro-pyridin-2-yl)-[1,4]diazepan-1 -y!]-ethyl}-phenoxy)-benzothiazole; [(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl~amino]-acetic acid ethyl ester; 1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethylH1 ,4']bipiperidinyi-4-carboxylic acid ethyl ester; l42-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1!4']bipiperidinyl-4-carboxylic acid; {2-[4-(Benzothiazol-2-yioxy)~pheny!]-ethyl}-cyclopropy!-ethy!-amine; 3-({2-[4-(Benzothiazol-2-yloxy)~phenyi]-ethyl}-cyclopropyI-amino)-2-methyl-propionic acid trifluoromethansulfonic acid salt; 2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-ethanot; 2-[2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-cyclopropy!methyl-amino)-ethoxy3-ethanol; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyI-amino)-propan-1-ol; Docket PRD2089PCT 544938 {2-[4-(Benzothiazol-2-yloxy)-phenyl|-ethyl}-cyclopropy!methyl-(3-tetrazol-2-yl-propyl)-amine; {2-[4-(Benzothiazol-2-yloxy)~phenyi]-ethyl}-cyclopropyl-(3-pyrroi-1-yl-propyl)-amine; 4-{{2-[4~{Benzothiazo!-2-yloxy)-phenyl3-ethyl}-cyclopropylmethyl-amino)-butyronitrile; 1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidine-4-carboxyiic acid (2-cyano~ethyl)-amide; {2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-cycIopropyimethyI-[3-(2H-tetrazol-5-yl)-propy[]-amine; 3-[5-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yi)-tetrazol-1-yij-propionitrile; {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyt}-cyclopropyl-[3-(2H-tetrazol-5-yl)-p ropylj-am i ne; 1-{2~[4-{Benzothiazol-2-yloxy)-phenyiJ-ethyl}-piperidine-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide; {2-[4-(BenzothiazoI-2~yloxy)~phenyI]-ethyl}-cyclopropylmethyl-[3-(1 H-[1,2,4]triazof-3-yl)-propylJ-amirie; {2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-cyc!opropyimethyl-[3-(5-methy!-1 H-[1 ^^Jtriazol-S-ylJ-propyO-amine; {2-[4-(Berizothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyimethy!-[3-(5-phenyl-1 H-[1,2,4]triazol-3-yl)-propyi]-amine; 2-(4-{2-[4-{1-Methyl-1H-tetrazoi-5-y))-piperidin-1-yi]-ethyI}-phenoxy)-benzothiazole; 2-{4-{2-[4-(2-Methyl-2H-tetrazof-5-y!)-piperidin-1-yl]-ethy!}-phenoxy)-benzothiazole; 1-{2-[4-(Benzothiazol-2-yloxy)-pheny!}-ethyi}-piperidine-4-carbonitrile; 2.(4-{2"[4-{1H-[1,2,3]Triazol-4-yi)-piperidiri-1-yl]-ethyl}-phenoxy)-benzothiazole; 4-{2-[4~(Benzothiazol-2-yloxy)-phenyt]~ethylarnino}-butyric acid ethyf ester; Docket PRD2089PGT 544938 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]~ethyl}-cycIopropylmethyl-amino)-butyric acid ethyl ester; 2-[3-({2-[4-{Benzothiazol-2-y!oxy)-phenyl]-ethyl}-cyclopropylmethyi--amino)-propyl]-isoindole-1,3-dione; 4-{{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyimethyl-amino)-butyric acid; 1-{3-{2-[4-{Benzothiazol-2-y!oxy)-phenyi]-ethyiamino}-propyl)-pyrrotidin-2-one; N-1-{2-[4-(Benzothiazoi-2-yloxy)-phenyi]-ethyl}-N1-cyciopropylmethyl-propane-1,3-diamine; 5-{{2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino) pentanoic acid methyl ester; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}~ cyclopropylmethyl-amino)-propy!]-acetamide; Morpholine-4-carboxylic acid [3-{{2-[4-(benzothiazol-2-yioxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)"propyl]-amide; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyclopropylmethyi-amino)-propyl]-methanesulfonamide 5-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyc!opropyl~amino)-pentanoic acid; 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropy!-amino) propyl]-pyrroiidin-2-one; 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-pyrroiidin-2-one; 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyl-amtno)-propyl]-pyrrolidin-2-one; 1-[3-({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-propyi-amino)-propyl]-pyrrolidin-2-one; 4-({1-AcetyI-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-amino)-butyric acid ethyl ester; 4-((1-Acetyi-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-amino)-butyric acid ethyl ester; Docket PRD2089PCT 544938 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-methanesuIfonyi-amino)-butyric acid; ({2-[4-(Benzothiazol-2-yioxy)-phenyi]-ethyl}-cyc!opropy!-amino)-acetic acid; 6-{{2-[4-(Benzothiazo!-2-yioxy)-phenyl]-ethyl}-cyclopropyl-amino) hexanoic acid ethyf ester; 7-{{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyciopropyl-amino) heptanoic acid ethyf ester; 6-({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyI-amino) hexanoic acid; 7-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cycIopropyi~amino)-heptanoic acid; N-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N1-cyclopropyi-propane-1,3-diamine; N-[3-({2-[4-(Benzothiazo[-2-yloxy)-phenyi]-ethyl}-cyc!opropyl-amino)-propyl]-acetamide; N-[3-({2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-cyc!opropyi-amino)-propyl]-isobutyramide; N-[3-({2-[4-(BenzothiazoS-2~y!oxy)-phenyl]-ethyi}-cyclopropyS-amino)-propyl]-benzamide; N-[3-({2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-4-chloro-benzamide; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropyi-amino)-propyl]-methanesulfonamide; Propane-2-sulfonic acid |>({2-[4-(benzothiazo[-2-yloxy)-phenyl]-ethyl}~cyc!opropyl-amino)-propyi]-amide trifluoromethansulfonic acid salt; 8-({2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethy!}-cyclopropyi-amino)-octanoic acid ethyl ester; 1-[3-{{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyi]-3-phenyl-urea; 8-({2-(4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyciopropyl-amino}- octanoic acid; Oh 355 ' W 2 3 APR Docket PRD2089PCT 544938 Tetrahydro-furan-2-carboxylic acid [3-({2-[4-(benzothiazol-2- yloxy)-phenyi]-ethyi}-cyclopropyl-arnino)-propyt]-amide; N-[3-({2-(4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-cyclopropyl- amino)-propylj-2-hydroxy~acetamide; 4-({2-[4-(Benzothiazot-2-yloxy)-phenoxy]-ethyl}-cyciopropyl- amino)-butyric acid; 2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzothiazoie; 2-[4-(2-Piperidin-1-yl~ethoxy)-phenoxy3-benzothiazole. 64. A pharmaceutical composition as in claim 46, wherein said at least one compound of formula (II) is one of: 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol; {2~[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyi-amine; Cyclohexyl-ethyl-{2-[4-(1 -methyl-1 H-benzoimidazoi-2-yloxy)-phenyl]-ethy!}-amine; 1 -{2-[4-(1 H-Benzoimidazol-2-yloxy)-phenoxy]-ethy!}-4-{4-bromo-phenyi)-piperidin-4-oi; 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-piperidin-4-ot; 1-{2-[4-{1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-o!; {2-[4~(1H-Benzoimidazol-2-yloxy)-phenyl]-ethy]}-cyclohexyl-ethyl-amine; 2-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenoxy]-1 H-benzoimidazole; 2-[4-(2-Azepan-1-yl-ethy!)-phenoxy]-1 H-benzoimidazole; {2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyi}-d!butyl-amine; 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyi}-piperidin-4-ol; 1-{2-E4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester; {2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethy!}-cyciohexyl-ethyl-amine; 356 Docket PRD2089PCT 544938 2-{4-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-1 H-benzoimidazole; 2-{4-[2-(2-Ethyl-piperidin-1 -yl)-ethoxy]-phenoxy}-1 H-benzoirnidazole; 2-[4-(2-Piperidin-1 ~yi~ethoxy)-phenoxy]-1 H-benzoimidazote; 1 -{2-[4-(1 H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-pipehdin-4-ol; 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-1 H-benzoimidazole amide; {3-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine; 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-1 H-benzoimidazole; {2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-diethyi-amine; 2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-1H-benzoimidazole; 2-[4-(2-Piperidin-1 -yl-ethyl)-phenoxy]-1 H-benzoimidazoie; 1-(1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin- 4-yi)-pyrroiidin-2-one; (1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-yt)-methano[; and 1-{2-[4-(1H-Benzoimidazol-2-y!oxy)-phenoxy]-ethyi)-piperidine-4-carboxylic acid ethyl ester. 65. A pharmaceutical composition as in claim 46, wherein said at least one compound of formula (I) is at least one compound of formula (IN): \ / 5 (ill) 357 Docket PRD2089PCT 544938 or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof, wherein R4, R6, X, Y, Z, and W are defined as in compound of formula (1), R2 is defined 5 as R2 in compound of formula (I), and R3 is defined as R3 in compound of formula (I), provided that (a) said R2 and R3 further satisfy one of the following: (e1): at least one of said R2 and R3 is not Chalky!, when Z is O and X is S; 10 (e2): none of R2 and R3 is Ct-4alkylC(0)Rx, with Rx being one of Ci_ 4alkyl, OH, -OCi-4alkyl, -OC0-4alkylRAr, or -NRYRY, when Y is Os Z is bond, and R2 is different from R3; and (e3): none of R2 and R3 is-Ci-ealkylCN, when Y is O, Z is bond, and R2 is different from R3; and 15 (b) further provided that when X is S, Y is O, Z is bond, and W is CH2, then one of R2 and R3 is not XCG when the other is Chalky I, wherein XCG is the group "i CH2 -4 (XCG) HC16 20 wherein HC16 is one of H, Chalky!, haloCi-galkyl, ailyl, and C^alkoxymethyl, and GO is a group attached by a carbon member that has a =0 substituent forming an amido group with the nitrogen member to which said GO group is attached. 25 66. A pharmaceuticai composition as in claim 65, wherein said R4 is H. 358 / % ,x 2 3 APR 20G9 | ^ ^ClJ Docket PRD2089PCT 544938 10 15 20 25 67. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are each independently selected from the group consisting of A), B), C), D), E), and I), as defined in claim 46, 68. A pharmaceuticai composition as in claim 65, wherein said R2 and R3 are each independently selected from the group A), as defined in claim 46. 69. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are each independently selected from the group B), as defined in claim 46. 70. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are each independently selected from the group C), as defined in claim 46. 71. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are each independently selected from the group D), as defined in claim 46. 72. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are each independently selected from the group E), as defined in claim 46. 73. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are each independently selected from the group I), as defined in claim 46. 74. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of i) and ii), as defined in claim 46. 75. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group i), as defined tn claim 46. 359 Docket PRD2089PCT 544938 76. A pharmaceutical composition as in claim 65, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said 5 attachment nitrogen, said heterocyclic ring being selected from the group ii), as defined in claim 46. 77. A use according to claim 1 substantially as herein described with reference to any example thereof. 10 78. A pharmaceutical composition according to claim 46 substantially as herein described with reference to any example thereof. 360 Docket PRD2089PCT 79. A compound of formula (f I): W N 10 15 20 or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceutically acceptable salt, ester, or amide thereof, wherein X is selected from the group consisting of NR5, O, and S, with R5 being one of H and CH3; Y is selected from the group consisting of CH2, and O; Z is selected from the group consisting of O and bond; W is selected from the group consisting of CH2 and CHR1-CH2! with R1 being one of H and OH, wherein the Reattached carbon member in said CHR1-CH2 is not directly attached to the nitrogen member to which said W is attached; R4 is selected from the group consisting of H, OCH3, CI, F, Br, I, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 is defined as R2 and R3 is defined as R3, as follows: R2 and R3 are each independently selected from the group consisting of A) H, Chalky!, C3_7alkenyl, wherein the carbon in said alkenyl that is attached to the nitrogen member has only single bonds, C3-7alkynyl, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, C3_7cycloaikyl optionally benzofused, Cs-7cycloalkenyl, -C3-7cycloalkylCi_7alkyl, ~Ci-7alkylC3.7cycloalkyl and phenyl, wherein each of the substituents A) is independently substituted with 0, 1, or 2 R°, and each of said R° is a substituent at 361 Docket PRD2089PCT 10 15 20 25 a carbon member that is at least one carbon member removed from the nitrogen member; B) a substituent HetRa; C) "C1.7a!kylC(0)Rx, optionally substituted with CH2RAr or CH2RA^; D) -C2„5alkylC(0)Rx, wherein two valence allowed carbon members in the C2-5alkyl of said -C2-5alkylC(0)Rx are part of a saturated C3_ 6carbocycle; E) ~C2-5alkylOH wherein two valence allowed carbon members in the C2.5alkyi of said -C2.5alkylGH are part of a saturated Cs-ecarbocycie; F) -Ccwaikylphenyl, wherein the phenyl in said -Co-4alkyiphenyi is fused at two adjacent carbon members in said phenyl to Rf, or is benzofused; G) -Co^alkylAr6, where Ar6 is a 6-membered heteroaryl having a carbon member point of attachment and having one or two ~N= heteroatom members, and benzofused; H) -Co-4alkylAr5, where Ar5 is a 5-membered heteroaryl, having one heteroatom member selected from the group consisting of O, S, and >NRy, and having 0 or 1 -N= additional heteroatom member, optionally containing two carbonyl groups, and optionally benzofused; I) -Gi-4a!kylAr5, where Ar5 is a 5-membered heteroaryl containing 3 or 4 nitrogen members, optionally substituted with RY, and having a valence allowed site as a point of attachment; J) -Co-4alkylAr6"6, where Ar6"6 is a Co-4alkyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has one or two -N= heteroatom members; K) -Co-4alkylAr6"5, where Ar6"5 is a C0-4alkyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRY, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is -N-; and L) one of 2-(4~ethyl-phenoxy)-benzothiazofe, 2-(4-ethyl-phenoxy)-benzooxazole, and 2-(4-ethyl-phenoxy)-1 H-benzoimidazole; 362 .Xlj ok Docket PRD2089PCT M) S02C^alkyi; alternatively R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected 5 from the group consisting of i) a 4-7 membered heterocyclic ring HetRb, said 4-7 membered heterocyclic ring HetRb having one heteroatom member that is said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different substitution members, 10 said substituents being selected from the group consisting of -Ry, -CN, -C(0)Ry, -C0-4alkylCO2RY, -C0-4alky!C(O)CO2RY, -C0. 4alkylORY, -C0-4alkyiC(O)NRYRz -Co~4aikylNRYC(0)Rz, -C(0)NRz0RY -C0-4alkylNRYC(O)CH2ORY1 -C0-4aIkylNRYC(O)CH2C(O)RY -C0-4a!kylNRYCO2RY, -15 Co-4alkylNRYC(0)NRYRz, -C0-4alky!NRyC(S)NRYRz, -NRYC(0)C02RY -NRyRz -Co-4alkyiNRwS02RY!1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-RY-1H-tetrazol-5-yi, RY-triazolyl, 2-RY-2H-tetrazol-5-yl, pyrrolidine-2-thion-1-yl, piperidine-2-thion-l-yl, -20 C0-4alkylC(O)N(RY)(SO2RY), -C0-4aiky[N(RY)(SO2)NRYRY -C0- f\j-CN (s|-CN N'R N 4alky!N(RT)(S02)NRTC02Rr, halo, H H , H n-CN N-oh v! ii „ ^ .... N O- RY ^m^C-RY H , and Ry h ; ii) a 5-7 membered heterocyclic ring HetRc, said 5-7 heterocyclic ring HetR° having one additional heteroatom 25 member separated from said attachment nitrogen by at least one carbon members, said additional heteroatom member being selected from the group consisting of O, S(=0)o-2. and >NRM, said 5-7 membered heterocyclic ring HetRc having 0 or 1 carbonyl members, and being Docket PRD2089PCT substituted with 0, 1, or 2 substituents at the same or at different carbon substitution members, said substituents being selected from the group consisting of -C{0)RY -C02Ry ~C3~4afkyiC02RY and Rz; 5 iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazoi-1-yI, imidazol-1-yl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yI, pyrroi-1-yl, 2-pyrroiin-1-yl, and 3-pyrrolin-1-yl, wherein each of said 2H-tetrazol-2-yl and 1H-tetrazol-1-yl is substituted at the carbon member with 0 or 1 of-Co-4a[kylRz, -Co~4a[ky(SRY, -10 Co-4alkylC02RY, and substituent HetRa; and iv) one of 1,2,3,4-tetrahydro-quinoiin-1-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yi, indol-1 ~yl, isoindol-2-yl, indolin-1-yi, benzimidazoi-1-yl, 2,8-diaza-spiro[4,5]decan-1-one-8-yl, 4-{[(2-tert-butoxycarbonyiamino-cyclobutanecarbony!)~ 15 amino]-methyl}-piperidin-1-yi, 4-{[(2-amino- cyclobutanecarbonyi)-amino]-methyl}-piperidin-1 -yl, 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yl tert-butyl ester, 4-oxo-1-phenyl-1,3t8-triaza-spiro[4.51dec-8-yl, and 4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl; 20 wherein substituent HetRa is a 4-7 membered heterocyclic ring having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from said carbon member point of attachment by at least 1 additional carbon 25 member; Rk is selected from the group consisting of H, -Ci^afkyl, -Co-4aikylRAr each optionally substituted with 1, 2, or 3 substituents Rn Rl is selected from the group consisting of -C02Rs and -C(0)NRsRs; RM is selected from the group consisting of Rz, indol-7-yi, -S02RY, -C3-30 4alkylC02RY, -C02RY, -C(0)NRz0RY, -C(0)RY, -C{0)Ci.4alkyl0RY, - Co-4alkyfC(0)NRsRs , C0-4alkylC(O)CO2RY! 1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-y!, 1-RY-1H-tetrazol-5-yl, 364 * Docket PRD2089PCT 544938 RY-triazoiyl, 2-RY-2/-/-tetrazol-5-yI and -CfMalkyiC(0)N(RY)(S02RY), each optionally substituted with 1, 2 or 3 substituents RN; RN is selected from the group consisting of OCH3, C!, F, Br, I, OH, NH2, CN, CF3, CH3, 0C(0)CH3, and N02; 5 Rq is selected from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, trichloromethyl, -CN, -Chalky!, -Co-4alkylRAr, -C0-4alky!RAr, -C0-4alky!ORY, -C0.4alkylCO2RY, -C0-4alkylNRYRz, -C0^alkylNRYCORY! -C0-4alkylNRYCONRYRz, -C0-4alkylNRYSO2RY, and -C0»4alkylSRY; Rs and Rs are independently selected from the group consisting of H, 10 -C^alkyl, and -C0-4alkylphenyl; alternatively, Rs and Rs are taken together with the nitrogen member to which said Rs and Rs are attached to form a 4-7 membered heterocyclic ring having 0 or 1 additional heteroatom member selected from the group consisting of O, S, and >NRY, provided that said additional heteroatom member is separated by at least two carbon 15 members from said nitrogen member to which said Rs and Rs are attached, and provided that where RY is Co-4alkylRAr, then RAr is not substituted with RL; Rw is selected from the group consisting of RY, and -C3.7cycioalkyl; Rx is selected from the group consisting of ~ORY, -NRYRZ, -Ci.4alkyl, and 20 -C(MalkylRAr; Ry is selected from the group consisting of H, -Ci-4alkyl, -C0-4a!kylRAr and -Co^alkylR^, each optionally substituted with 1, 2, or 3 substituents Rn; Rz is selected from the group consisting of RY, -C2-4alkylORv, -C1-2alkyiC02RY, -Cv2aikylC(0)NRsRs', and -C2.4alkylNRsRs'; 25 when RY and Rz are attached to a nitrogen member, RY and Rz are selected as defined above, or RY and Rz are taken together with the RY- and Rz-attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group consisting of O, S, and >NRM, said 4-7 membered heterocyclic ring HetRd 30 having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring 365 V M>R • Docket PRD2089PCT 544938 10 15 20 25 HetRd having 0 or 1 vaience allowed carbon members substituted with at least one of RM, -CC^H, and -C0-ialkylORY; RAris a moiety with a carbon member attachment point and said moiety is selected from the group consisting of phenyl, pyridyl, pyrimidyi, and pyrazinyl, wherein each valence allowed carbon member in each of said moieties is independently substituted with at least one of 0, 1, 2 or 3 RN, and 0 or 1 RL; RAf is a 3-8 membered ring, having 0, 1 or 2 heteroatom members selected from the group consisting of 0, S, N, and >NRY, having 0, 1, or 2 unsaturated bonds, having 0 or 1 carbonyl members, wherein each valence allowed member in each of said rings is independently substituted with 0, 1, or 2 Rk; and Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members; provided that (a) at least one of said R2 and R3 is not ethyl when one selection in the group consisting of selections (s1), (s2), (s3), and (s4), is satisfied, and each of said selections is specified as (s1); R4isH, ZisO, W is CH2, Y is CH2, and X is S; (s2): R4 is H, Z is O, W is CH2, Y is CH2, and X is NH; (s3): R4 is H, Z is O, W is CH2, Y is O, and X is S; (s4): R4 is 5-chloro, Z is O, W is CH2, Y is CH2, and X is S; (b) further provided that when Z is bond, Y is CH2, W is CHR1-CH2, R1 is H, and one of R2 and R3 is 1 H-imidazol-2-yl, then the other of R2 and R3 is selected from A1), B)-L), wherein B)-L) are as defined above for compound of formula (I), and A1) consists of H, C37alkenyl, wherein the carbon in said C3. 7alkeny! that is attached to the nitrogen member has only single bonds, C3. 7aikynyl, wherein the carbon in said aikynyl that is attached to the nitrogen member has only single bonds, C3.7cycloalkyi optionally benzofused, C5. 7cycloaikenyl, -C3-7cycloalkylCwalkyl, -Ci.7alkylC3.7cycloalkyl; and (c) further provided that when X is S, Y is O, Z is bond, and W is CH2, then one of R2 and R3 Is not XCG when the other is Ci.6alkyl, wherein XCG is the group 366 Docket PRD2089PCT 544938 CN N GO (XCG) HCI 6 10 15 20 wherein HC16 is one of H, Chalky), haloC-^alkyl, aiiyl, and C^salkoxymethyl, and GO is a group attached by a carbon member that has a =0 substituent forming an amido group with the nitrogen member to which said GO group is attached. 80. A compound as in claim 79, wherein said R4 is H. 81. A compound as in claim 79, wherein said R2 and R3 are each independently selected from the group consisting of A), B), C), D), E), and I), as defined in claim 79. 82. A compound as in claim 79, wherein said R2 and R3 are each independently selected from the group A), as defined in claim 79. 83. A compound as in claim 79, wherein said R2 and R3 are each independently selected from the group B), as defined in claim 79. 84. A compound as in claim 79, wherein said R2 and R3 are each independently selected from the group C), as defined in claim 79. 85. A compound as in claim 79, wherein said R2 and R3 are each independently selected from the group D), as defined in claim 79. 86. A compound as in claim 79, wherein said R2 and R3 are each independently selected from the group E), as defined in claim 79. 367 Docket PRD2089PCT 544938 87. A compound as in claim 79, wherein said R2 and R3 are each independently selected from the group f), as defined in claim 79. 88. A compound as in claim 79, wherein said R2 and R3 are taken together 5 with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of i) and ii), as defined in claim 79. 10 89. A compound as in claim 79, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group i), as defined in claim 79. 15 90. A compound as in claim 79, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group ii), as defined in claim 79. 20 91. A compound as in claim 79, wherein said compound of formula (II) is one of: 2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-benzooxazole; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]ethyl}-piperidin-4-yl)- methanol; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin~4-oi; {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dibutyi-amine; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yi)-methanol; 1-{3-[4-(Benzooxazoi-2-yloxy)-phenoxy]-propyl}-4-phenyi-piperidin~ 4-ol; 1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-benzyi-piperidin~ 4-oi; 2-[4-(2-Pipertdin-1 -yl-ethyl)-phenoxy]-benzooxazoie; 368 /§ V ( 2 3 APS 2909 \ J Docket PRD2089PCT 544938 {3-[4-{Benzooxazoi-2-yloxy)-phenyl]-propyl}-cyc!ohexyl-ethyl-amine; 1-{3-[4-(BenzooxazoI-2-yloxy)-phenyl]-propyI}-piperidirv4~ol; 1-{3-[4-(Benzooxazof-2-yloxy)-phenoxy]-2-hydroxy-propyl}»4- phenyl-piperidin-4-oI; 1-[2-(4-Benzooxazo]-2-ylmethyl-phenoxy)-ethylj-piperidine-4-carboxyiic acid ethyl ester; 2~[4-(2-Pyrrolidin-1 -yl-ethoxy)-phenoxy]-benzooxazole; {3-[4-(Benzooxazo[-2-yloxy)-phenoxyj-propyl}~dimethyl-amine; {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine; and 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzooxazole. 92. A compound as in claim 79, wherein said compound of formula (II) is one of: 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyi-piperidin~ 4-ol; {2-[4-(Benzooxazol~2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine; 2-{4-[2-(2-Ethyl-piperidin-1-yl)~ethoxy]-phenoxy}-benzooxazo(e; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]~ethyI}-4-phenyl-piperidine-4-carbonitrile; 1-(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyI}-4-phenyl~ piperidin-4-yl)-ethanone; 2~{4~[2-(4~Methyl-piperidin-1-yl)"ethoxy]-phenoxy}-benzooxazole; 1-{2-[4-(Benzooxazo!-2-yioxy)-phenoxy]-ethyl}«4-(4-chloro-phenyf)- piperidin-4-oi; 1-{2-[4-(Benzooxazoi-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol; 1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-3-trifluoromethyl~phenyl)-piperidin~4-ol; 1-{2~[4-(Benzooxazoi-2~yloxy)-phenoxy]~ethyl}~4-benzyi-piperidin-4-ol; 369 Docket PRD2089PCT 544938 {2-[4-(Benzooxazol~2~yloxy)-phenoxy]-ethyl}-cyclohexyl-methyl-amine; and {2-[4-(Benzooxazol-2-yloxy)-phenoxy3-ethyl}-cycfopropylmethyl~ propyl-amine. 93. A compound as in claim 79, wherein said compound of formula (II) is one of: {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-butyl-ethyi-amine; 2-({2-[4-(Benzooxazoi~2~yloxy)~phenoxy]~ethyl}-benzyi-amino)-ethanol; 2~{4-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-phenoxy}-benz'ooxazole; (1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3-yl)- methanol; 2-({2~[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyi}-propyl~amino)-ethanol; 2-[4-(2-Azetidin-1-yl-ethoxy)-phenoxy]-benzooxazole; A/-(1-{2-[4-(Benzooxazol~2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-2- phenyl-acetamide; 1-{2-[4-(Benzooxazo!-2-yloxy)-phenoxy]-ethyl}~piperidine-3-carboxylic acid ethyl ester; 2-{4-[3-(4-Phenyl-piperidin-1-y!)-propoxy]-phenoxy}-benzooxazole; 1_{2-[4-{Benzooxazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ol; {2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-cydohexyl-ethyl-amine; 2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzooxazole; and 2-[4-(2-Azepan-1 -yl-ethyl)-phenoxy]-benzooxazole. 5 94. A compound as in claim 79, wherein said compound of formula (II) is one of: {2-[4-(Benzooxazol~2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyl-amine; 370 x; /$ V f 2 3 APR 2909 Docket PRD2089PCT 544938 {2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-dibutyi-amine; 1-{2-[4-(Benzooxazol-2-yloxy)-pheny!]-ethyl}-piperidin-4»ol; 1-{2-[4-(Benzooxazoi-2-yloxy)-phenyi]-ethyi}-piperidine~4~ carboxylic acid methyl ester; 1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-4-phenyl-piperidin-4-ol; 2-[4-(3-Piperidin-1-yl-propyl)-phenoxy]-benzooxazole; {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-dibutyl-amine; {3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cyclopropylmethyi-propyl-amine; 1-[4-(Benzooxazol-2-yloxy)-phenoxy]-3-pyrrolidin-1-yl-propan-2-ol; 1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-4-pheny!- piperidin-4-ol; 1-[2-(4-Benzooxazoi-2-ylmethyI-phenoxy)-ethyl]-piperidine-4-carboxylic acid amide 2-[4~(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzooxazole; arid {2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-diethyl~amine. 95, A compound as in claim 79, wherein said compound of formula (II) is one of: {2-[4-(6-Chloro-benzothiazoi~2-yloxy)-phenoxy]~ethyl}-diethyi-amine; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol; 1-{2-[4-(Benzothiazol-2-yloxy)~phenoxy]-ethyl}-piperidine-4-carboxylic acid ethyl ester; 1-{2~[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy3-ethyl}-piperidin-4-yl)-pyrrolidin-1-yl-methanone; 3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-propionic acid ethyl ester; 1-{2-[4-(Benzothiazol-2-yioxy)-phenoxy]-ethyl}-piperidine-4-carboxylic acid amide; 371 Docket PRD2089PCT 544938 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]~ethyl}-piperidin-4-yl)-pyrrolidin-2-one; 1'-{2-[4-(Benzothiazol-2-yloxy)~phenoxy]-ethyl}-[1 4'jbipiperidinyl 2-one; 8-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,8-diaza-spiro[4.5]decan-1-one; 2-[4-(3-Pyrrolidin-1-yl-propoxy)-pherioxy]-benzothiazo!e; {2-[4-(Benzotbiazol-2-yloxy)-phenyi]-ethyl}-cyciohexyl-ethyi-amine; 1-{2-[4-(Benzothiazol-2-y!oxy)-pheriyt3-ethy!}--piperidine-3-carboxyfic acid amide; 1 -{1 -{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-pipersdin-4-yl)-3-methyf-1 ,3-dihydro--benzoirriidazol-2-one; 1-{2-f4-{Benzothiazol-2-yloxy)-pheny!]-ethyl}-piperidine-4-carboxylic acid methyl ester; (1~{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidiri-4-yl)~(4-methyl-piperaziri~1~yl)-methanone; 1-f2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylic acid methyl ester; 3-({2-[4-(Benzothiazol-2-y!oxy)-pherioxy]-ethyl}-cyclopropy!-amirto)-propionic acid; {2-[4-(Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-dimethyl-amirie; 2-[4-{2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzothiazole; {3-[4-(Berizothiazo!-2-yloxy)-phenoxy]-propyl}~dimethyi-amine; 2-[4-(2-Azepan-1-y[-ethoxy)-phertoxy]-benzothiazole; 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-benzothiazole; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyt}-4-phenyl-piperidin 4-ol; {2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclohexy[-ethyl-amine; 1-{2-[4-(Benzothiazol~2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-pheny!)-piperidin-4-oi; {2-[4-{Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-dibuty!-amine; 372 Docket PRD2089PCT 544938 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}~4-(4-bromo~ phenyl)-pipericfin-4-ol; 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxyj-ethyl}-4-(4-chioro-3-trifluoromethyl-phenyl)-piperidin-4-ol; 1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-berizy!-piperidin-4-ol; I'^-j^HBenzothiazol^-yloxy^phenoxyj-ethylHMlbipiperidirse; (1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)- methanol; /V-(1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin~4~yl)~ 2-pheny!-acetamide; 2-(4-{2-[4-(2-Morpholin-4-yl-ethy!)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazole; 2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethyi}-phenoxy)-benzothiazole; 1-{3-[4-(Benzothiazol-2-yloxy)-phenoxy]-propyl}-4-phenyl-piperidin-4-oI; 1-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyi}-4~pheny[~piperidin-4-ol; 2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzothiazole; 2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzothiazole; {2-[4-(Benzothiazol-2-yloxy)~phenyl]-ethyl}-cyclopropylmethyl-propyl-amine; {2-t4-(Benzothiazol-2-yloxy)-phenyl3-ethyl}-dibutyl-amine; 2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-benzothiazoIe; 1-{2-[4-(Benzothiazol-2-yIoxy)-phenyl]-ethyl}-piperidin-4-ol; 1-{2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid amide; 1-{2-[4-(Benzothiazol-2-yloxy)-pbenyj]-ethyl}-piperidine~3-carboxyiic acid ethyi ester; 1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-4-phenyi-piperidine-4-carboxylic acid ethyl ester; 373 4V* I Docket PRD2089PCT 544938 (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-acetic acid ethyl ester; 1-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethy!}-piperidin-4-yl)-1,3-dihydro-indot-2-one; 1-(1-{2-[4-{Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-yl)-pyrrolidin-2-one; /\/-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-2-phenyl-acetamide; B-^-^Benzothiazol^-yloxyJ-phenyO-ethyij-^S-diaza-spiro[4.5]decan-1-one; 1-{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-piperidin-3-ol; 1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidine-4-carboxylic acid ethyl ester; 1'-{2-f4-(Benzothiazol»2-yloxy)-phenyl]-ethylH114,]bipiperidine; 2-{4~[2-(4-MethyI-piperazin-1-yl)»ethyl]-phenoxy}-benzothiazole; 2-(4-{2-[4-(1 -Benzyi-1 H-tetrazol-5-yl)-piperidin-1 -yl]-ethoxy}-phenoxy)-benzothiazole; 4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-piperazine~1-carboxylic acid ferf-butyl ester; 1-[2-(4-Benzothiazo1-2-ylmethyl-phenoxy)-ethyi]~piperidine-4-carboxylic acid amide; 1-{1-[2-(4-Benzothiazol-2-ylmethyj-phenoxy)-ethyl]-piperidin-4-yl}-pyrrolidin-2-one; -j „[4_( 1 ~{2~[4-(Benzothiazol-2»yloxy)-pheny|]-ethyl}-piperid ine-4-carbonyl)-piperazin-1-yl]-ethanone; 1-{2-[4-{BenzothiazoI-2-yioxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid; 1-(1-{2-[4-(Benzothiazot-2-yloxy)-phenoxy]-ethyi}-piperidin-4-y!)-pyrrolidine-2-thione; 2-(4-{2-[4-(Benzothiazot-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)~ ethanol; 2-(4-{2-[4-(Benzothiazol~2-yloxy)-phenoxyj~ethyl}-piperazin-1-yl)- 1 -pyrroiidin-1 -yl-ethanone; 374 Docket PRD2089PCT 544938 2-{4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy3-ethyl}-piperazin-1~yl}-1 -morpholin-4-yl-ethanone; 1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]~ethyl}»piperidine-3-carboxylic acid; 1 -{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethy!}-piperidine-2-carboxylic acid; (1-{2-[4-(Benzothiazol-2-y[oxy)-phenyi]-ethyl}-piperidin-3-yi)-acetic acid; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yi)~ acetic acid ethyl ester; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-y!)-carbamic acid tert-butyl ester; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-aceticacid; (1-{2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-piperidin-3-yl)-methanol; {{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-cyclohexyl-amino)-acetic acid methyl ester; (4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-y!)-acetic acid; 1-(1-{2-[4-(Benzothiazoi-2-yloxy)-phenoxyj-ethyl}-piperidin-4-yI)-5-oxo-pyrroiidirie-2-carboxylic acid ethyl ester; l-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-5-oxo-pyrrolidine-2-carboxylic acid; 4-(4-{2-[4-(Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-phenol; A/»(1-{2-[4-(Benzothiazol-2-yloxy)-pherioxy]~ethyi}-piperidin-4-yl)-4-chloro-/V-cyclopropyl~benzene sulfonamide; 3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethy!}~ cyciopropylmethyl-amino)-propionic acid; 3-{{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-isopropyi-amino)-propionic acid; 375 2 3 APR 10 Docket PRD2089PCT 544938 1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl amine; 3-[{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}--(1-rnethyl-piperidin-4-yl)-amino]-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-benzyi-amino)-propionic acid; 3-{(1-Acetyi-piperidin-4-yl)-{2-[4-(benzothiazol-2-yioxy)-phenoxy]-ethyi}-amino)-propionic acid; 4-(1-{2-[4-(Benzothiazof-2-yloxy)-phenoxy]-ethyi}-1 H-tetrazoi-5-yl)-piperidine-1 -carboxylic acid tert-butyl ester; 3-({2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyl}-cyciopropyl-amino)-propionic acid; 3-{(1-AcetyI-piperidin~4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethy!}-amino)-propionic acid; 3-[{2-[4»(Benzothiazo[-2-ytoxy)-phenyi]-ethyl}-(1-methyi-piperidin- 4-yl)-amino]-propionic acid; 3-({2-[4-(Benzothiazol-2-yioxy)~phenyl]-ethyl}-cyclopropyImethyl-amino)-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-isopropyi-amino)-propionic acid; 2-(4-{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperazin-1-yl)-1-pyrroiidin-1-yl-ethanone; (R)-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxyiic acid; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenylj-ethyl}-piperidin-4-yf)-1,3-dihydro-benzoimidazol-2-one; 2-(4-{2-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yi]-ethyi}-phenoxy)-benzothiazole; 2-{4-[2-{4-Ethanesulfonyi-piperazin-1-yl)-ethyl]-phenoxy}-benzothiazole; 2-(4-{2-[4~(Benzothiazol-2-yioxy)-phenyi]-ethyl}-piperazin-1-yi)-1-morpholin-4-yi-ethanone; 376 Docket PRD2089PCT 544938 3-({2-[4"(Benzothiazol~2-yloxy)-phenyi]~ethyl}-methyl-amino)-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopentyi-amino)~ propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclobutyl-amino)-propionic acid; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyf}-benzyl-amino)-propionic acid; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yi)-(4- hydroxymethyl-piperidin-1-yl)-methanone; {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropy!-amine; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yi)-[4- (2-hydroxy-ethyl)-piperazin-1-yi]-methanone; (1-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-(4- (2-hydroxy-ethyl)-piperidin-1-yl]-methanone; 2-({2-[4-(Benzothiazo1-2~yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-ethanol; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyc!opropyI-amino)-propan-1-oi; 4-({2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyi}-cyc!opropyi-amino)-butyric acid; 3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyi)-amino]-propionic acid; 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}~cyclopropyi~amino)-butyronitrile; 3-(1-{2-[4-(Benzothiazo[-2-yloxy)-phenyl]-ethyl}-piperidin-4-yi)-propionic acid; [{1-{2-[4-(Benzothiazoi-2-y!oxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl-amino]-acetic acid; 3-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}--piperazin-1-yi)-phenot; 2-(4-{2-[4~{4-Methoxy-pbenyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazoie; 377 /w f-§ ( 2 3 APS 2TO9 Docket PRD2089PCT 544938 2-{4-[2-(5-Piperidin-4-yl-tetrazoi-1-y!)-ethoxy]~phenoxy}- benzothiazole; (S)-1-(1-{2-[4-(Benzothiazol-2~yloxy)-phenoxyj-ethyl}-piperidin-4~ yl)~4-hydroxy-pyrroiidin~2-one; {2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amine; 2-[({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cycIopropyl-amino)-methyl]-cyc!opropanecarboxylic acid ethyl ester; 4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy3-ethyi}-piperazine-1-carbortyl)-benzoic acid ethyl ester; 2-[({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-methylj-cyciopropanecarboxylic acid; 1-({2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-cyclopropyl-amino)-propan-2-oi; 3-({2-[4-(Benzothiazol~2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-1,1,1-trifluoro-propan-2-ol; 3-{{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propionamide; 3-({2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propane-1,2-diol; 2-{4-[2-{5-Phenyl-tetrazol-2-yl)-ethoxy3-phenoxy}-benzothiazole; 2-{4-[2-{5-Phenyl-tetrazol~1~yl)-ethoxy]-phenoxy}-benzothiazole; A/-{2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-/V-cyclopropyi-2-(2H-tetrazol-5-yl)-acetamide; (S)-3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methyl-propan-1 -oi; (R)-3-({2-[4-(Benzothiazoi-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methyl-propan-1-ol; 2-{4-[2-(5-Methylsulfanyl~tetrazol~2~yi)-ethoxy]-phenoxy}-benzothiazole; 2-{4-[2-(5-Methylsulfanyl~tetrazol-1~yl)~ethoxy]-phenoxy}-benzothiazole; 2-[4-(2-Tetrazol-2-yl-ethoxy)-phenoxy]-benzothiazole; 378 % fw I 2 3 APR 2009 Docket PRD2089PCT 544938 2-[4-(2-T etrazol-1 -yl-ethoxy)~phenoxyj-benzothiazole; (1R,2R)-2-{2-[4-(Benzothiazol-2-y!oxy)-phenyl]-ethylamirio}-cyclohexanecarboxylic acid; (1S,2R)~2-{2-[4-(Benzothiazol-2-yloxy)-phenylJ-ethylamino}~ cyclohexanecarboxyiic acid; (1Rs2R)'2-{2-[4-(Benzothiazol-2-yloxy)-pheriyl]-ethylamino}-cyclohexanol; {1S,2R)-2-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethylamino}-cyclohexanol; 4-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-yl)-butyric acid; (R) 1 -(1 -{2-[4-(Benzothiazol-2-ytoxy)-p'henoxy]-ethyl}-piperidin-4-yi)-4-hydroxy-pyrrolidin-2-one; 2-(4-{2-[4-(1H-Tetrazol-5-yi)-piperidin-1~yi]-ethyi}-phenoxy)-benzothiazoie; (1-{2-[4-(Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yl)-methanol; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazoi-5-yl)-acetic acid ethyl ester; (1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazol-5-yj)-acetic acid ethyl ester; 2-{4-[2-(5-Piperidin-4-yl-tetrazoi-2-yl)-ethoxy]-phenoxy}-benzothiazole hydrochloride; 7-{2-[4-(Benzothiazol-2-yloxy)-phenoxyJ-ethyl}-4-spiro-[3-phthalidej-piperidine; 1~{3~[4~(Benzothiazoi-2-yloxy)-phenyl]-propyl}-piperidine~4-carboxylic acid ethyl ester; 2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamine hydrochloride; 2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yl]-ethoxy}-phenoxy)-benzothiazofe; cis-4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxyltc acid trifluoromethanesulfonate salt; 379 2 3 APR 2003 Docket PRD2089PCT 544938 {4~{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-(tetrahydro-furan-2-y!)~methanone; Propane-2-sulfonic acid (1-{2-[4~(benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amide; (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperazin-1-y!)-oxo-acetic acid methyl ester; N-{1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyi)-benzenesulfonamide trifluoromethanesulfonate sait; N-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidsne-4-carbonyl)-methanesulfonamide trifiuoromethanesuifonate sait; {4-{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperazin-1-y!)-oxo-acetic acid trifluoromethanesulfonate salt; (4-{2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-morpholin-4-yl-methanone; 1-(4-{2-[4-(Benzothiazoi-2~yloxy)-phenyl]-ethyl}-piperazin-1~yl)~2~ thiophen-2-yl-ethanone; (4-{2-[4-(Benzothiazoi-2-yloxy)~phenyl]-ethyl}-pjperazin-1-y!)-pyridin-3-yl-methanone; (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-cyciopropyl-methanone; 1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-y!)-2-methoxy-ethanone; 1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2,2s2-trifluoro-ethanone; 4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazine-1-carbonyi)-benzoic acid; (4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-pyridin-4-yl-methanone; (4»{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperazin-1-yl)-{5-methyl-pyrazin-2-yl)-methanone; (f?)-{4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yi)-(tetrahydro-furan-2-yl)-methanone; 380 Docket PRD2089PCT 544938 {$)-(4-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-{tetrahydro-furan-2-yl)-methanone; (4-{2~[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}~piperazin~1-y!)-(tetrahydro-furan-3-yf)-methanone; 1-(4-{2-[4-(Berizothiazol-2-yloxy)-phenyl]-ethyl}~piperazin-1-yl)-2-hydroxy-ethanone; 2-[2-(4-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperazin-1-yl)- 2-oxo-ethyl]-cyclopentanone; 3-(4-{2-[4-{Benzothiazo!-2-yloxy)-phenyl]-ethyi}-piperaziri-1-yi)-propionic acid trifluoromethanesufonate salt; 3-(1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidin-4-yl)-oxazoiidin-2-one; 4~(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-morpholiri-3-one; 4-(1-{2-[4-(Benzothiazol-2~yioxy)-phenoxy]-ethyl}-piperidin-4-y!)-morpholin-3-one; 3-(1-{2-|4-{Benzothiazoi-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yI)-oxazolidin-2-orie; 1-{2-[4-(Benzothiazol-2-yloxy)-phenyI]-ethyl}-p iperid ine-4-carboxylic acid benzyioxy-amide; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidin-4-yI)-acetic acid; {R)-1-(1-{2-[4-(Benzothiazol-2-ySoxy)-phenyl]-ethy!}-piperidin-4-yl)-4~hydroxy-pyrrolidirv2-one; 1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidirte-4-carboxylic acid hydroxyamide; (S)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-y!)- 4-hydroxy-pyrrolidin-2-one; (1-{2-[4~(Benzoth!azol-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-carbamic acid tert-butyl ester; 2-{4-[2~(4-Fluoro-piperid!n-1-yl)-ethyl]-phenoxy}-benzothiazoie; 2-{4-[2-(4l4-Difluoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazole; (R)-1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-pyrrolidiri-3-ol; 381 Docket PRD2089PCT 544938 N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-piperidin-4-yl)-formamide; (1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-urea; 1 -(1 -{2-[4-(Benzoth iazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-phenyt-isourea; 1-{1-{2-[4-(Bertzothiazoi-2-yloxy)-phenyi]-ethyl}-piperidin-4-yl)-3-cyano-2-methyl-isothiourea; N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyI}-piperidin-4-yl)-methanesulfonamide; 1-(1-{2-[4-(Benzothiazol-2™yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-methyl-guanidine; 8-{2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-1-phenyi-1,3,8-triaza-spiro[4.5]decan-4-one; 8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-1,3,8-triaza-spiro[4.5]decane-2,4-dione; (1-{2'[4-(Benzothiazol~2~yloxy)-phenyl]-ethyl}-piperidin-4»yl)-methyt-carbamic acid tert-butyl ester; n-(1-{2-[4-(Benzothiazol~2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-n-rriethyl-acetamide; N-(1-{2-[4-(Benzoth!azol-2-yloxy)-phenyl]-ethyi}-piperidin-4-yl)-N-methyl-methanesulforiamide; Acetic acid [(1-{2-[4-(benzothiazol-2-y!oxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-carbamoy!]-methyl ester; n-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-n- acetamide; Acetic acid {1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethy!}-piperidin-4-ylcarbamoyl)-methyl ester; 2-({2-[4-(Benzothiazol-2-y!oxy)-phenylj-ethyl}-methyl-amirio)-3-(1H-imidazol-2-yl)-propioriic acid; 2-(4-{2-[4-{3-Nitro~pyrtdin-2-ylH1,4]diazepan~1~yl]~ethyl}~ phersoxy)~benzothiazole; [(1-{2-[4~(Berizothiazol~2-yloxy)-phenoxy]-ethyl}-piperidine-4» carbonyl)-methyl-amino]-acetic acid ethyl ester; 382 V 2 3 apr ,<5/ Docket PRD2089PCT 544938 T-{2-[4-{Benzothiazol-2-yloxy)-phenoxy]-ethyi}-[1,4']bipiperidinyl-4-carboxylic acid ethyl ester; 1,-{2-[4-(Berizothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4']bipiperidinyl-4-carboxylic acid; {2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyl}-cyclopropyl-ethyl-amine; 3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methyl-propionic acid trifluoromethansulfonic acid salt; 2-({2-[4-{Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyclopropyimethyl-amino)-ethanol; 2-[2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cycIopropylmethyl-amino)-ethoxy]-ethanol; 3-({2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propan-1-ol; {2-[4-(Benzothiazo!-2-yloxy)~phenyl]~ethyl}~cyclopropylmethyl-(3-tetrazol-2-yl-propyl)-amine; {2-[4-(Benzothiazol~2-yloxy)-phenyl]-ethyl}-cyclopropyl-(3-pyrroI-1-yl-propyl)-amine; 4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-butyronitrile; 1-{2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-piperidine-4-carboxyfic acid (2-cyano-ethyl)-amide; {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropylmethyl-[3-(2H-tetrazol-5-yl)-propyl]-amjne; 3-[5-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yI)-tetrazol-1 -ylj-propionitrile; {2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethyl}-cyclopropyl-[3-(2H-tetrazol-5-yl)-propyl]-amine; 1-{2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyi}-piperidine-4~ carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide; {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(1 H-[1,2,43triazol-3-yi)-propyl]-amine; 383 Docket PRD2089PCT 544938 {2-[4-(Benzothiazol-2-yloxy)-pheny!]~ethyl}~cyclopropyIrnethyi~[3-(5-methyl-1 H-[1,2,4]triazol~3~yl)~propyl]-amine; {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-cyciopropyimethyl-[3-(5-phertyl-1 H-[1,2,4]triazof-3-yl)-propyI]-amine; 2-(4-{2-[4-(1-Methyl-1H-tetrazol-5-yl)-piperidin-1-yl]-ethy!}-pherioxy)-benzothiazole; 2-(4-{2-[4-(2-Methyl-2H-tetrazol-5-yl)-piperidiri-1-yi]-ethyl}-phenoxy)-benzothiazo!e; 1-{2-[4-(Benzothiazol-2-y!oxy)-pheriyl]-ethyl}-piperidine-4-carbonitrile; 2-(4-{2-[4-(1H-[1,2,3]Triazol-4-yi)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazoie; 4-{2-[4-(Benzothiazol-2-yloxy)-phenyi]-ethylamino}-butyric acid ethyl ester; 4-{{2-[4-{Benzothiazo!-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-butyric acid ethyl ester; 2-[3-({2-|4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropylmethyl-amirio)-propy!]~isoindole-1,3~dione; 4-({2-[4-(Benzothiazol-2-yloxy)-pheny!]-ethyl}-cyciopropy!methyl-amino)-butyric acid; 1-(3-{2-[4-{Benzothiazol-2-yloxy)-pheriyl]-ethy(amino}-propyl)-pyrro!idin-2-one; N-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N1-cyclopropylmethyl-propane-1,3-diamine; 5-({2-[4-{Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-perttanoic acid methyl ester; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyimethyi-amino)-propy!]-acetamide; Morphoiine-4-carboxylic acid [3-({2-[4-(benzothiazol~2~yioxy)~ pheny!j-ethyl}-cyclopropylmethyi-amino)-propyl]~amide; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}~ cyciopropylmethyi-amino)-propy!]~methanesulfonamide 384 Docket PRD2089PCT 544938 5-({2-[4-{Benzothiazol-2-yloxy)~phenyi]~ethyl}~cyciopropyt-amino)-pentanoic acid; 1-[3-({2-[4-(Benzothiazol-2~yloxy)-phenyl]-ethyl}-isopropyl-amino)-propyi]-pyrrolidin-2-one; 1-[3-({2~[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyciopropy!methyl-amino)-propyl]-pyrrolidin-2-one; 1-[3-({2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyciopropyl-amino)-propyl]-pyrrolidin-2-one; 1-[3-{{2-[4-(Benzothiazoi-2-yloxyJ-phenyl]-ethyl}-propyi-amino)-propy(]-pyrrolidin-2-one; 4-({1-AcetyI-piperidin-4-yi)-{2-[4-(benzothiazol-2-yloxy)-phenyi]-ethyl}-amino)-butyric acid ethyl ester; 4-((1-Acetyl-piperidin-4-y!)-{2-[4-(benzothiazol-2-y!oxy)-pheny!]-ethy!}-amino)-butyric acid ethyl ester; 4~({2-[4-(Benzothiazol-2-yloxy)~phenyl]~ethyl}-methanesu!fony!-amino)-butyric acid; ({2-[4-(Benzothiazol-2-yioxy)-phenyI]-ethyl}-cyclopropyl~amino}-acetic acid; 6-({2-[4-(Benzothiazol-2-yioxy)-phenyl]-ethyl}-cyciopropyi-amino)-hexanoic acid ethyl ester; 7-({2-[4-(Benzothiazol-2-yloxy)~pheny[]-ethyl}-cyclopropyl-amino)-heptanoic acid ethyl ester; 6-({2-[4-{Benzothiazol-2-yloxy)-phenyI]-ethyl}-cyc!opropyf-amino)-hexanoic acid; 7-({2-[4-(Benzothiazo!-2-yloxy)-phenyl]-ethyi}-cyclopropyl-amino)-heptanoic acid; N-1-{2-[4-(Benzothiazo!-2-yloxy)-phenyi]-ethyl}-N1-cyclopropyl-propane-1,3-diamine; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-acetamide; N-[3~({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclop.ropyl-amino)-propyl]-isobutyramide; 385 3 v 2 3 APR 2BC9 ] £\J Docket PRD2089PCT 544938 N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyI-amino)-propyl]-benzamide; N~[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyI-amino)-propyl]-4-chloro-benzamide; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-methanesulfonamide; Propane-2-sulfonic acid [3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-amide trifluoromethansulfonic acid salt; 8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl~amino)~ octanoic acid ethyl ester; 1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-3-phenyl-urea; 8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-octanoic acid; Tetrahydro-furan-2-carboxylic acid [3-({2~[4-(benzothiazol~2- yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-amide; N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyi}-cyclopropyl- amino)-propyl]-2-hydroxy-acetamide; 4-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyl- amino)-butyric acid; 2-[4-{2-Morpholin-4-yl-ethoxy)~phenoxy]-benzothiazole; 2-[4~(2-Piperidin-1 -yl-ethoxy)-phenoxy]-benzothiazole. 96. A compound as in claim 79, wherein said compound of formula (II) is one of: 1 -{2-[4-( 1 H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol; {2-[4-{1H~Benzoimidazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyl-amine; Cyclohexyi-ethyl-{2-[4-(1 -methyl-1 H-benzoimidazol-2-yloxy)-phenyl]-ethyl}-amine; 386 Docket PRD2089PCT 544938 1~{2-{4~(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol; 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyI}-4-(4-chloro-phenyl)-piperidin-4-ol; 1 -{2-[4-(1 H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol; {2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine; 2-[4-(2-Pyrrolidiri-1-yt-ethyi)-phenoxy]-1/-/-benzoimidazole; 2-[4-{2-Azepan-1-yl-ethyl)-phenoxy]~1 H-benzoimidazole; {2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyi}-dibutyl-amine; 1~{2-[4-{1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ol; 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic acid methyl ester; {2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine; 2-{4-[2-{4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-1H-benzoimidazole; 2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]-phenoxy}-1H-benzoimtdazoie; 2-[4-{2-Piperidin-1 -yl-ethoxy)-phenoxyl-1 H-benzoimidazole; 1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyi}-piperidin-4-ol; 2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-1 H-benzoimidazole amide; {3-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine; 2-[4-(2-Pyrrolidin-1 -yl-ethoxy)-phenoxy]-1 H-benzoimidazole; {2-[4-{1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-diethyi-amine; 2~[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-1 H-benzoimidazole; 2-[4-(2-Piperidin-1 -yl-ethyl)-phenoxy]-1 H-benzoimidazole; 1 -{1 -{2-[4-( 1 H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-y!)-pyrrolidin-2-one; 387 '.s? 11 Docket PRD2089PCT 544938 (1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-y!)-methanol; and 1 -{2-[4-( 1 /-/-Benzoimidazo!-2-yloxy)-phenoxy]-ethyl)-piperidine-4-carboxylic acid ethyl ester. 388 Docket PRD2089PCT 97. A compound of formula (III): 5 (III) or an enantiomer, diasteromer, racemic, tautomer, hydrate, solvate, or a pharmaceuticafly acceptable salt, ester, or amide thereof, wherein X is selected from the group consisting of NR6, O, and S, with R5 being one of 10 H and CH3; Y is selected from the group consisting of CH2, and O; Z is selected from the group consisting of O and bond; W is selected from the group consisting of CH2 and CHR^c^, with R1 being one of H and OH, wherein the Reattached carbon member in said CHR1-CH2 15 is not directly attached to the nitrogen member to which said W is attached; R4 is selected from the group consisting of H, OCH3, CI, F, Br, I, OH, NH2, CN, CFs and CH3; R6 is H or F; and R2 is defined as R2 and R3 is defined as R3, as follows: 20 R2 and R3 are each independently selected from the group consisting of A) H, Ci.7alkyl, C3..7alkenyl, wherein the carbon in said alkenyl that is attached to the nitrogen member has only single bonds, C3„ 7aikynyl, wherein the carbon in said alkynyl that is attached to the nitrogen member has only single bonds, C3.7cycloalkyl optionally 25 benzofused, C5..7cycloalkenyl, -C3,.7cycloalkylCi.7aIkyl, -C^alkylCs. 7cycloalkyl and phenyl, wherein each of the substituents A) is Docket PRD2089PGT 544938 10 15 20 25 independently substituted with 0, 1, or 2 R°, and each of said RQ is a substituent at a carbon member that is at least one carbon member removed from the nitrogen member; B) a substituent HetRa; C) -Ci-7alkylC{0)R,NRY, and having 0 or 1 -N= additional heteroatom member, optionally containing two carbonyl groups, and optionally benzofused; I) -Ci-4alkylAr5, where Ar5 is a 5-membered heteroaryl containing 3 or 4 nitrogen members, optionally substituted with RY, and having a valence allowed site as a point of attachment; J) -Co-4alkylAr6 6S where Ar6 6 is a CQ„4alkyl-attached phenyl fused at valence allowed sites to a 6-membered heteroaryl, wherein said 6-membered heteroaryl has one or two -N= heteroatom members; K) -Co^alkylAr6"5, where Ar6*5 is a Co^aikyl-attached phenyl fused at valence allowed sites to a 5-membered heteroaryl, said 5-membered heteroaryl having one heteroatom member selected from the group consisting of O, S, and >NRY, and said 5-membered heteroaryl having 0 or 1 additional heteroatom member which is -N=; and 390 Docket PRD2089PCT 544938 L) one of 2-(4-ethyl-phenoxy)~benzothiazole, 2-{4-ethyl~ phenoxy)-benzooxazole, and 2-(4-ethyl-phenoxy)-1 /-/-benzoimidazole; M) S02Ci.4aikyl; alternatively R2 and R3 are taken together with the nitrogen to which they are 5 attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group consisting of i) a 4-7 membered heterocyclic ring HetRb, said 4-7 membered heterocyclic ring HetRb having one heteroatom member that is 10 said attachment nitrogen, and being substituted with 0, 1, or 2 substituents at the same or at different substitution members, said substituents being selected from the group consisting of -Ry, -CN, -C(0)Ry, -C^4a!kylC02RY, -C0^alkylC(O)CO2RY, -C0. 4alkylORY, -C0-4alkyiC(O)NRYRz, -CQ-4alky!NRYC(0)Rz -15 C(0)NRz0RY, -Co-4alkylNRYC(0)CH2C>RY - C0-4alkylNRYC(O)CH2C(O)RY, -C0.4aikylNRYCO2RY, -C0-4atkylNRYC(O)NRYRz, -C0.4alkyINRYC(S)NRYRz -NRYC(O)CO2RYrNRYRz,-C0-4aikylNRwSO2RY1l3-dihydro-. indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, 20 tetrazol-5-yl, 1-RY-1H-tetrazol~5-yl, RY-triazoIyi, 2-RY-2H- tetrazol-5-yl, pyrrolidine-2-thion-1-yl, piperidine-2-thion-1-yl, -C0-4alkylC(O)N(RY)(SO2RY), -C0.4alkylN(RY)(SO2)NRYRY, -C0. n-CN n-CN ^N' uin'^A nV N' ^N^S-rY 4alkylN(R )(S02)NR C02R , halo, H H , H N^CN N'0H \ pY N — RY H ,and R ; 25 it) a 5-7 membered heterocyclic ring HetRc, said 5-7 heterocyclic ring HetRc having one additional heteroatom member separated from said attachment nitrogen by at least one carbon members, said additional heteroatom member being selected from the group consisting of O, S(=0)n.?, and >NR 391 2 3 APR M r'-vX- Docket PRD2089PCT 544938 said 5-7 membered heterocyclic ring HetRc having 0 or 1 carbonyl members, and being substituted with 0, 1, or 2 substituents at the same or at different carbon substitution members, said substituents being selected from the group 5 consisting of -C(0)Ry, -C02RY -C3-4alkylC02RY and Rz; iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazol-1-yl, imidazol- 1 -yl, 2/-/-tetrazol-2-yi, 1H-tetrazol-1-yl, pyrrol-1-yl, 2-pyrrolin-1-yl, and 3-pyrrolin-1-yl, wherein each of said 2H-tetrazol-2-yl and 1H-tetrazol-1-yl is substituted at the carbon member with 10 0 or 1 of -C0-4aiky!Rz, -C0-4aikylSRY, -C0-4alky!CO2RY, and substituent HetRa; and iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl, 1,2,3,4-tetrahydro- isoquinolin-2-yl, indol-1-yl, isoindoi-2-yl, indolin-1-yl, benzimidazol-1-yl, 2,8-diaza-spiro[4,5jdecan-1-one-8-yl, 4-15 {[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]- methyl}-piperidin-1-yl, 4-{[(2-amino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl, 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yl tert-butyl ester, 4-oxo-1 -phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl, and 4-oxo-1,3,8-triaza-spiro[4.5]dec-20 8-yl; wherein substituent HetRa is a 4-7 membered heterocyclic ring having a carbon member point of attachment and containing a member >NRM as a heteroatom member, and said heteroatom member being separated from 25 said carbon member point of attachment by at least 1 additional carbon member; Rk is selected from the group consisting of H, -C-^alkyl, -C0-4atkylRAr each optionally substituted with 1, 2, or 3 substituents RN RL is selected from the group consisting of-C02Rs and -C(0)NRsRs; 30 RM is selected from the group consisting of Rz, indol-7-yl, -S02RY, -C3. 4alkylC02RY, -C02RY, -C(0)NRz0RY, -C(0)RY, -C(0)Ci.4alkyl0RY, -Co-4alkyIC(O)NRSRS, C0-4alkylC(O)CO2RY, 1,3-dihydro-indol-2-one-.1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl, 1-Ry-1 392 Docket PRD2089PCT RY-triazofyl; 2~RY-2/-/~tetrazol-5-yi and -C0„4alky!C(O)N(RY)(SO2RY), each optionally substituted with 1, 2 or 3 substituents RN; Rn is selected from the group consisting of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3i 0C(0)CH3, and N02; 5 Rq is selected from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, trichloromethyl, -CN, -Chalky!, -Co-4aiky!RAr, -Co^alkylRAf, -C0.4a!kylORY, -C0-4alkylCO2RYJ -C0-4alkylNRYRz, -C0-4a!kyiNRYCORY, -C0-4alkylNRYCONRYRz, -C0-4aIkylNRySO2Ry, and -C0-4alky!SRY; Rs and Rs are independently selected from the group consisting of H, 10 -Ci^alkyl, and -Co-4alkylphenyl; alternatively, Rs and Rs are taken together with the nitrogen member to which said Rs and Rs are attached to form a 4-7 membered heterocyclic ring having 0 or 1 additional heteroatom member selected from the group consisting of O, S, and >NRY, provided that said additional heteroatom member is separated by at least two carbon 15 members from said nitrogen member to which said Rs and Rs are attached, and provided that where RY is Co-4alkylRAr, then RAr is not substituted with Rl; Rw is selected from the group consisting of RY and -C3_7cycloalkyi; Rx is selected from the group consisting of-ORY, -NRyRz, -Chalky!, and 20 -C0-4aikylRAr; Ry is selected from the group consisting of H, -C^alkyl, -C0-4aikylRAr and -Co-4alkylRAr, each optionally substituted with 1,2, or 3 substituents RN; Rz is selected from the group consisting of RY, -C2.4alkylORY, -C1„2alkylC02RY-Ci„2aSkylC(0)NRsRs, and -C2-4alky!NR£Rs; 25 when Ry and Rz are attached to a nitrogen member, RYand R2 are selected as defined above, or Ry and Rz are taken together with the RY- and Rz-attached nitrogen member to form a 4-7 membered heterocyclic ring HetRd having 0 or 1 additional heteroatom members selected from the group consisting of 0, S, and >NRM, said 4-7 membered heterocyclic ring HetRd 30 having 0 or 1 carbonyl members, and said 4-7 membered heterocyclic ring 393 m l3 API 2909 Docket PRD2089PCT 544938 HetRd having 0 or 1 valence allowed carbon members substituted with at least one of RM, -CO2H, and -Co-ialkylORY; RAris a moiety with a carbon member attachment point and said moiety is selected from the group consisting of phenyl, pyridy!, pyrimidyl, and 5 pyrazinyl, wherein each valence allowed carbon member in each of said moieties is independently substituted with at least one of 0, 1, 2 or 3 RN, and 0 or 1 RL; RAf is a 3-8 membered ring, having 0, 1 or 2 heteroatom members selected from the group consisting of O, S, N, and >NRY, having 0, 1, or 2 10 unsaturated bonds, having 0 or 1 carbonyl members, wherein each valence allowed member in each of said rings is independently substituted with 0, 1, or 2 Rk; and Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members; 15 provided that (a) said R2 and R3 further satisfy one of the following: (e1): at least one of said R2 and R3 is not C15alkyl , when Z is O and X is S; (e2): none of R2 and R3 is Ci-4alkylC{0)Rx[ with Rx being one of C1. 20 4alkyl, OH, -OCi.4alkyi, -OC0-4alkylRAr, or -NRYRY( when Y is O, Z is bond, and R2 is different from R3 ; and (e3): none of R2 and R3 is -Ci-6alkyiCN, when Y is O, Z is bond, and R2 is different from R3; and (b) further provided that when X is S, Y is O, Z is bond, and W is CH2, then one 25 of R2 and R3 is not XCG when the other is Chalky!, wherein XCG is the group CN i—f—CH2 ~k (XCG) -4 GO HC16 394 13 m a® Docket FRD2089PCT 544938 wherein HC16 is one of H, Ci.6alkyl, haloCi-6alkyi, ally!, and Ci-ealkoxymethyl, and GO is a group attached by a carbon member that has a =0 substituent forming an amido group with the nitrogen member to which said GO group is attached. independently selected from the group consisting of A), B), C), D), E), and I), 10 as defined in claim 97. 100. A compound as in claim 97, wherein said R2 and R3 are each independently selected from the group A), as defined in claim 97. 15 101. A compound as in claim 97, wherein said R2 and R3 are each independently selected from the group B), as defined in claim 97. 102. A compound as in claim 97, wherein said R2 and R3 are each independently selected from the group C), as defined in claim 97. 103. A compound as in claim 97, wherein said R2 and R3 are each independently selected from the group D), as defined in claim 97. 104. A compound as in claim 97, wherein said R2 and R3 are each 25 independently selected from the group E), as defined in claim 97. 105. A compound as in claim 97, wherein said R2 and R3 are each independently selected from the group I), as defined in claim 97. 30 106. A compound as in claim 97, wherein said R2 and R3 are taken together with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said 5 98. A compound as in claim 97, wherein said R4 is H. 99. A compound as in claim 97, wherein said R2 and R3 are each 20 395 2 3 m 219 Docket PRD2089PCT 544938 heterocyclic ring being selected from the group consisting of i) and ii), as defined in claim 97. 107. A compound as in claim 97, wherein said R2 and R3 are taken together 5 with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group i), as defined in claim 97. 108. A compound as in claim 97, wherein said R2 and R3 are taken together 10 with the nitrogen to which they are attached to form a heterocyclic ring that contains at least one heteroatom member that is said attachment nitrogen, said heterocyclic ring being selected from the group ii), as defined in claim 97. 396
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